Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.
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type of specification: points based system based on Tatvigian et al 2020
-clarified PS1 strong/moderate/supporting for non-canonical splice variants
-under PS3, edited “PVS1_strength (RNA)” to remove “strength”
-under PM1, removed Arg899Pro from the list of non-critical aa (also in BS3), fixed the Gly47Gln typo, and removed redundant lists of non-critical residues
-under BS1, fixed the ≥ symbol
-under BS2, added a moderate strength and adjusted the number of homozygotes for supporting and moderate
| Criteria & Strength Specifications
|
||||
|---|---|---|---|---|
| PVS1 | ||||
|
Original ACMG Summary
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease.
Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts.
VCEP Specifications:
Biologically relevant transcript: NM_001204.7. LOF variants 5' or at c.2816 (exons 1-12) are expected to undergo NMD. Variants 3' to c.2816 (exon 13) are not expected to undergo NMD. Exon 13 does not contain regions critical for protein function and encodes <10% of the protein. Variants p.Trp9* and p.Trp13* (W13*) are known to escape NMD and produce a truncated protein (PMID: 20095988). Critical regions for protein function: ligand binding domain (aa 33-131), kinase domain (aa 203-504), heterodimerization domain (aa 485-492), and transmembrane domain (aa 151-171). For canonical splice variants, RNA splicing assay data is not necessary for applying PVS1; follow the decision tree based on the predicted effect of disrupted splicing. Note that exons 2, 3, 4, 6 are in-frame and a loss of a canonical splice acceptor/donor is not expected to result in NMD. Non-canonical splice site variants with RNA splicing assay data may be applicable for PVS1 according to the decision tree. The initiation codon is located in exon 1. There are approximately 27 in-frame downstream AUG initiation codons including 5 sites located in ex 4-6 having translation initiation scores similar or greater than the exon 1 codon (PMID: 20095988). However, there are many P/LP variants upstream of exons 4-6. Stand Alone
Very Strong
Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats:
**Use the PVS1 decision tree guide.
Default Point Value:
8
Modification Type:
Gene-specific
Strong
Use the PVS1 decision tree guide.
Default Point Value:
4
Modification Type:
Gene-specific,Strength
Moderate
Use the PVS1 decision tree guide.
Default Point Value:
2
Modification Type:
Gene-specific,Strength
Supporting
Default Point Value:
1
Not Applicable
|
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| PS1 | ||||
|
Original ACMG Summary
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
VCEP Specifications:
PS1 can be applied to non-canonical splicing variants as specified below and according to guidelines by the ClinGen SVI Splicing Subgroup (PMID: 37352859). Prerequisite: the predicted event of the variant under assessment must precisely match the predicted event of the comparison (i.e both predicted to lead to exon skipping, or both to lead to enhanced use of a cryptic splice motif), AND the strength of the prediction for the variant under assessment must be of similar or higher than the strength of the prediction for the comparison variant. Stand Alone
Very Strong
Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
Default Point Value:
4
Modification Type:
None
Moderate
Same amino acid change as a previously established likely pathogenic variant regardless of nucleotide change. For splice variants outside splice donor/acceptor ± 1,2 dinucleotide positions but residing in the same splice donor motif (last 3 bases of the exon and intronic positions +3 to +6) or acceptor motif (first base of the exon and intronic positions -20 to -3) as a previously established pathogenic variant. The splice motif coordinates are as defined by Walker et al 2023 (PMID: 37352859).
Default Point Value:
2
Modification Type:
Strength
Supporting
For splice variants outside splice donor/acceptor ± 1,2 dinucleotide positions, same splice donor motif (last 3 bases of the exon and intronic positions +3 to +6) or acceptor motif (first base of the exon and intronic positions -20 to -3) as a previously established likely pathogenic variant. The splice motif coordinates are as defined by Walker et al 2023 (PMID: 37352859).
Default Point Value:
1
Modification Type:
Strength
Not Applicable
|
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| PS2 | ||||
|
Original ACMG Summary
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone
Very Strong
Default Point Value:
8
Strong
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity.
Default Point Value:
4
Modification Type:
No change
Moderate
Default Point Value:
2
Supporting
Default Point Value:
1
Not Applicable
|
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| PS3 | ||||
|
Original ACMG Summary
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established.
VCEP Specifications:
Can be applied additively with PP3 if applicable. Not applicable for splicing effects; consider PVS1 (RNA). Stand Alone
Very Strong
Default Point Value:
8
Strong
Use the BMPR2 functional assay document for guidance on allowable assays. The document is based on the recommendations by Brnich et al 2019 (PMID: 31892348). Known variant validation controls (i.e. established pathogenic and benign variants) are required. One exception is if the same functional assay has been performed for the same variant by two independent groups and demonstrated to have the same functional effect by both groups. Also applicable for non-canonical splice site variants when RNA splice site assay data is available demonstrating abnormal splicing; positive and negative controls are required, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.
Default Point Value:
4
Modification Type:
General recommendation,Gene-specific
Moderate
Default Point Value:
2
Supporting
Use the BMPR2 functional assay document for guidance on allowable assays as described above. If no known variant validation controls (i.e. established pathogenic and benign variants) were used, then score at the supporting strength.
Default Point Value:
1
Modification Type:
General recommendation
Not Applicable
|
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| PS4 | ||||
|
Original ACMG Summary
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence.
VCEP Specifications:
Affected individuals are defined as having a mean pulmonary artery pressure (mPAP) >20 mm Hg by right heart catheterization (RHC), or estimated by echocardiography if RHC is not advised. Strength is based on the number of unrelated PAH (heritable and/or idiopathic) probands identified with a variant. Unpublished, VCEP-approved internal case/variant data is acceptable if the proband does not have another pathogenic or likely pathogenic BMPR2 variant. Justification for the proband thresholds is provided in the “Data and citations related to PS4” attachment. PS4 (at any strength) and PM2_supporting can be used additively. Stand Alone
Very Strong
Default Point Value:
8
Strong
Prior observation of the variant in >4 unrelated patients with the same phenotype, and its absence in controls.
Default Point Value:
4
Modification Type:
Disease-specific
Moderate
Prior observation of the variant in >3 unrelated patients with the same phenotype, and its absence in controls.
Default Point Value:
2
Modification Type:
Disease-specific,Strength
Supporting
Prior observation of the variant in >1 unrelated patients with the same phenotype, and its absence in controls.
Default Point Value:
1
Modification Type:
Disease-specific,Strength
Not Applicable
|
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| PM1 | ||||
|
Original ACMG Summary
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
VCEP Specifications:
Well-established functional domains for BMPR2 include the extracellular (ligand-binding) domain, protein kinase domain, and heterodimerization motif within the kinase domain. Strong evidence based on evolutionary conservation, in vitro functional assays, and protein structural analyses indicates the critical (or non-critical) nature of specific amino acid residues within each of these domains (see attached “Data and citations related to PM1”). Strength should be applied accordingly. Stand Alone
Very Strong
Strong
Variant changes a critical amino acid. Extracellular domain: p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123. Kinase domain: p.Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Arg491. KD heterodimerization: p.Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Leu492. Note that Gly182Asp and Met186Val have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (PMID: 18321866) (apply BS3). We note that Glu503Asp has demonstrated lack of of effect on canonical signaling in one assay, this has not been replicated in an independent assay; in the absence of further investigation, this variant cannot be conclusively designated non-critical (do not apply BS3). While tested variants in the extracellular domain (p.Gln42Arg, Gly47Asn, Gln82His, Thr102Ala, Ser107Pro) have limited or no effect on canonical signaling, studies have indicated that they may play a role in disruption of non-canonical/SMAD-independent pathways (PMIDs: 14583445 and 16002577). In the absence of further investigation, these variants cannot be conclusively designated non-critical (do not apply BS3).
Default Point Value:
4
Modification Type:
Gene-specific,Strength
Moderate
Variant changes an amino acid in the extracellular domain (aa 33-131) or kinase domain (aa 203-504) but without functional evidence indicating critical or non-critical.
Default Point Value:
2
Modification Type:
Gene-specific
Supporting
Default Point Value:
1
Not Applicable
|
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| PM2 | ||||
|
Original ACMG Summary
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Caveat: Population data for indels may be poorly called by next generation sequencing.
VCEP Specifications:
PAH has a prevalence of 15-50 cases/million individuals and the population allele frequency threshold for PM2 is based on this frequency. There is no evidence for a genetic ancestry effect on PAH prevalence, so the use of any sub-population data is acceptable (as long as there is a minimum allele count of 1,000). As specified by the SVI WG, PM2 is scored at the supporting level only. Note that PM2_supporting and PS4 (at any strength) can be used additively. Stand Alone
Very Strong
Strong
Moderate
Default Point Value:
2
Supporting
Present at <0.01% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts. Caveat: Population data for indels may be poorly called by next generation sequencing.
Default Point Value:
1
Modification Type:
Disease-specific
Not Applicable
|
||||
| PM3 | ||||
|
Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase. Stand Alone
Very Strong
Default Point Value:
8
Strong
Default Point Value:
4
Moderate
Default Point Value:
2
Supporting
Default Point Value:
1
Not Applicable
Comments:
PAH is autosomal dominant.
|
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| PM4 | ||||
|
Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Default Point Value:
2
Modification Type:
No change
Supporting
Default Point Value:
1
Not Applicable
|
||||
| PM5 | ||||
|
Original ACMG Summary
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Also applicable for variants affecting the same splice site as a confirmed splice variant with similar or worse splicing in silico predictions
Default Point Value:
2
Modification Type:
General recommendation
Supporting
Novel missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before.
Default Point Value:
1
Modification Type:
Strength
Not Applicable
|
||||
| PM6 | ||||
|
Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
Stand Alone
Very Strong
Default Point Value:
8
Strong
Default Point Value:
4
Moderate
Default Point Value:
2
Supporting
Default Point Value:
1
Not Applicable
Comments:
Confirmation of maternity and paternity is required.
|
||||
| PP1 | ||||
|
Original ACMG Summary
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Note: May be used as stronger evidence with increasing segregation data.
VCEP Specifications:
Note: PAH exhibits variable age of onset and incomplete penetrance. Three levels of evidence are applied based on autosomal dominant likelihood ratios of 10 (3 meioses, LOD 0.9, supporting), 30 (5 meioses, LOD 1.5, moderate), and 100 (7 meioses, LOD 2.1, strong) provided that PM2 (absent or rare in large population cohorts) is met. Demonstration of segregation in more than one family is not necessary as BMPR2 is a well-established PAH gene. PMID: 29300372. Stand Alone
Very Strong
Strong
Co-segregation with disease in ≥7 affected family members.
Default Point Value:
4
Modification Type:
Strength
Moderate
Co-segregation with disease in ≥5 affected family members.
Default Point Value:
2
Modification Type:
Strength
Supporting
Co-segregation with disease in ≥3 affected family members.
Default Point Value:
1
Modification Type:
Strength
Not Applicable
|
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| PP2 | ||||
|
Original ACMG Summary
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
VCEP Specifications:
BMPR2 has a z-score of 3.28 for missense variants which is above the threshold of 3.09 (PMID: 40496714) for constraint. Stand Alone
Very Strong
Strong
Moderate
Supporting
PM2_supporting and PP3 must be met.
Default Point Value:
1
Modification Type:
Gene-specific
Not Applicable
Comments:
BMPR2 is not constrained for missense variants.
|
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| PP3 | ||||
|
Original ACMG Summary
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
Default Point Value:
2
Supporting
Two out of three REVEL/AlphaMissense/CADD predictor scores must meet the thresholds for supporting as specified in Pejaver 2022 PMID: 36413997 (CADD) and Bergquist et al 2025 PMID: 40084623 (AlphaMissense, REVEL). CADD ≥25.3, AlphaMissense ≥0.792, REVEL ≥0.644. The criterion can also be used for non-canonical splice variants if SpliceAI ≥0.2.
Default Point Value:
1
Modification Type:
General recommendation
Not Applicable
|
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| PP4 | ||||
|
Original ACMG Summary
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
Stand Alone
Very Strong
Strong
Default Point Value:
4
Moderate
Default Point Value:
2
Supporting
Default Point Value:
1
Not Applicable
Comments:
PAH does not have a single genetic etiology.
|
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| PP5 | ||||
|
Original ACMG Summary
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
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| BA1 | ||||
|
Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
Stand Alone
Allele frequency is above 1% in gnomAD, including any sub-population with at least 1,000 allele counts.
Default Point Value:
Not Applicable
Modification Type:
Disease-specific
Very Strong
Strong
Moderate
Supporting
Not Applicable
|
||||
| BS1 | ||||
|
Original ACMG Summary
Allele frequency is greater than expected for disorder.
Stand Alone
Very Strong
Strong
Allele frequency ≥0.1% among gnomAD controls, using the subpopulation with the highest frequency and at least 1,000 allele counts.
Default Point Value:
-4
Modification Type:
Disease-specific
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
|
||||
| BS2 | ||||
|
Original ACMG Summary
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
VCEP Specifications:
Strength based on number of homozygotes observed among gnomAD controls. Criteria not applicable for heterozygotes as BMPR2 variants exhibit incomplete penetrance. Stand Alone
Very Strong
Strong
Observed in ≥3 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).
Default Point Value:
-4
Modification Type:
Disease-specific,Gene-specific
Moderate
Observed in ≥2 homozygotes in gnomAD controls or reported in the literature (healthy adult individuals).
Default Point Value:
-2
Modification Type:
Disease-specific,Gene-specific
Supporting
Observed in ≥1 homozygote in gnomAD controls or reported in the literature (healthy adult individuals).
Default Point Value:
-1
Modification Type:
Disease-specific,Gene-specific
Not Applicable
|
||||
| BS3 | ||||
|
Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
VCEP Specifications:
Not applicable for splicing effects; replaced by BP7_strong (RNA). Stand Alone
Very Strong
Strong
Use the BMPR2 functional assay document for acceptable assays and guidance. Note that Gly182Asp and Met186Val have been demonstrated non-critical/not necessary for kinase activity based on a luciferase assay (apply BS3). We note that Glu503Asp has demonstrated lack of of effect on canonical signaling in one assay, this has not been replicated in an independent assay; in the absence of further investigation, this variants cannot be conclusively designated non-critical (do not apply BS3). While tested variants in the extracellular domain (p.Gln42Arg, Gly47Asn, Gln82His, Thr102Ala, Ser107Pro) have limited or no effect on canonical signaling, studies have indicated that they may play a role in disruption of non-canonical/SMAD-independent pathways (PMIDs: 14583445 and 16002577). In the absence of further investigation, these variants cannot be conclusively designated non-critical (do not apply BS3). Note that p.Cys34, Cys60, Cys66, Cys84, Cys94, Cys99, Cys116, Cys117, Cys118, Cys123, Gly210, Gly212, Lys230, Glu/Asn245, Asp333, Asn338, Asp351, Gly353 Glu386, Asp405, Gly410, Asp485, Gln486, Asp487, Ala488, Arg489, Ala490, Arg491, Arg491, and Leu492 have been demonstrated critical (apply PM1_strong).
Default Point Value:
-4
Modification Type:
Gene-specific
Moderate
Default Point Value:
-2
Supporting
For variants that have demonstrated limited or no effect on canonical signaling but not tested for effect on non-canonical/SMAD-independent pathways (PMID: 14583445 and 16002577).
Default Point Value:
-1
Modification Type:
Gene-specific,Strength
Not Applicable
|
||||
| BS4 | ||||
|
Original ACMG Summary
Lack of segregation in affected members of a family.
Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation.
VCEP Specifications:
Lack of disease segregation among BMPR2 variant carriers should not be scored due to low penetrance of PAH variants in families. Lack of variant segregation in affected family members should be scored. Stand Alone
Very Strong
Strong
Lack of variant segregation in affected members of a family.
Default Point Value:
-4
Modification Type:
No change
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
|
||||
| BP1 | ||||
|
Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Default Point Value:
-1
Not Applicable
Comments:
Both LOF and missense variants are known to cause PAH.
|
||||
| BP2 | ||||
|
Original ACMG Summary
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
VCEP Specifications:
Applicable if observed in cis with a P/LP BMPR2 variant in an individual with PAH. Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
No change - use as originally described
Default Point Value:
-1
Modification Type:
No change
Not Applicable
Comments:
BMPR2 variants are not fully penetrant.
|
||||
| BP3 | ||||
|
Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
In frame-deletions/insertions in a repetitive region without a known function.
Default Point Value:
-1
Modification Type:
No change
Not Applicable
|
||||
| BP4 | ||||
|
Original ACMG Summary
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
Two out of three REVEL/AlphaMissense/CADD predictor scores must meet the thresholds for supporting as specified in Pejaver 2022 PMID: 36413997 (CADD) and Bergquist et al 2025 PMID: 40084623 (AlphaMissense, REVEL). CADD ≤22.7, AlphaMissense ≤0.169, REVEL ≤0.29. The criterion can also be used for non-canonical splice variants if SpliceAI ≤0.1; can be applied in conjunction with BP7. For synonymous variants, CADD ≤22.7 is sufficient since REVEL and AlphaMissense are not applicable.
Default Point Value:
-1
Modification Type:
General recommendation
Not Applicable
|
||||
| BP5 | ||||
|
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
VCEP Specifications:
Can be applied when PVS1 or PM2 AND PP3 are not met and a pathogenic/likely pathogenic variant in a PH VCEP-defined definitive gene has been identified. Definitive genes include ACVRL1, ATP13A3, CAV1, EIF2AK4, ENG, GDF2, KCNK3, KDR, SMAD9, SOX17, and TBX4. Stand Alone
Very Strong
Strong
Default Point Value:
-4
Moderate
Default Point Value:
-2
Supporting
No change - use as originally described
Default Point Value:
-1
Modification Type:
No change,Strength
Not Applicable
Comments:
BMPR2 is the major causal PAH gene.
|
||||
| BP6 | ||||
|
Original ACMG Summary
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
Not Applicable
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
PubMed : 29543229
|
||||
| BP7 | ||||
|
Original ACMG Summary
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
VCEP Specifications:
Use default Splice AI predictions. Intronic variants outside of defined splicing motifs are applicable. (PMID: 37352859). Stand Alone
Very Strong
Strong
If BP7 is met and negative RNA splicing assay data is available, then apply BP7_strong. Acceptable splicing assays should have positive and negative controls, preferably from patients and matched unaffected individuals. Note that splicing assay results may be tissue-sensitive.
Default Point Value:
-4
Modification Type:
Strength
Moderate
Default Point Value:
-2
Supporting
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Applicable after assignment of BP4 for no adverse splicing predictions, and inclusive of exonic and intronic variants. Not applicable for synonymous variants located at the first base or the last three bases of an exon.
Default Point Value:
-1
Modification Type:
No change
Not Applicable
|
||||
| Category | Point Ranges |
|---|---|
| Pathogenic | 10 |
| Likely Pathogenic | 6 - 9 |
| Uncertain Significance | -1 - 5 |
| Likely Benign | -6 - -2 |
| Benign | -7 |
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Questions or comments?
