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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| Criteria & Strength Specifications
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| PVS1 | ||||
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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:
Use Hemoglobinopathy VCEP PVS1 decision tree. Loss of function has been established as a disease mechanism for haemoglobinopathies. 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 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.
Modification Type:
No change
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 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.
Modification Type:
Disease-specific,Gene-specific,Strength
Moderate
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 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.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Not Applicable
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| PS1 | ||||
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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:
A variant classification must have a minimum of two-star annotation in ClinVar to be considered established or VCEP consensus recommendation. Stand Alone
Very Strong
Strong
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Modification Type:
No change
Moderate
The same change of an amino acid shown to be a pathogenic variant in a paralogue gene.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Not Applicable
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| PS2 | ||||
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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.
VCEP Specifications:
Both maternal and paternal sample must be tested and shown to be the biological parents of the affected individual. Otherwise, identity is assumed, and not confirmed, and PM6 applies. Only applicable in the absence of any other established pathogenic variants. If other suspicious variants are present, then PM6 should be used instead. Should not be used in combination with PM6. Definition of trait phenotype is provided in the Appendix 3. Stand Alone
Very Strong
Strong
De novo (both maternity and paternity confirmed) in a patient with the disease or in a phenotypic trait individual 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.
Modification Type:
Disease-specific,Gene-specific
Moderate
Supporting
Not Applicable
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| PS3 | ||||
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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:
The list of approved functional studies is provided in the Appendix 2 (Functional Studies). Stand Alone
Very Strong
Strong
Moderate
Supporting
In vitro or in vivo functional studies supportive of a damaging effect on the gene, gene product, expression levels and protein function.
Modification Type:
Disease-specific,Gene-specific,Strength
Not Applicable
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| PS4 | ||||
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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. Stand Alone
Very Strong
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Strength evidence is determined by points according to Appendix 3. Very Strong evidence requires ≥16 points
Modification Type:
Disease-specific,Gene-specific,Strength
Strong
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Strength evidence is determined by points according to Appendix 3. Strong evidence requires 3.5-15.99 points
Modification Type:
Disease-specific,Gene-specific
Moderate
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Strength evidence is determined by points according to Appendix 3. Moderate evidence requires 1.5-3.49 points.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Strength evidence is determined by points according to Appendix 3. Supporting evidence requires 0.5-1.49 points
Modification Type:
Disease-specific,Gene-specific,Strength
Not Applicable
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| PM1 | ||||
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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.
Stand Alone
Very Strong
Strong
Moderate
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
Modification Type:
Disease-specific,Gene-specific
Supporting
Not Applicable
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| PM2 | ||||
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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:
Position of reported variant must have sufficient coverage (>= 20x) in the population database. Stand Alone
Very Strong
Strong
Moderate
Supporting
Allele frequency <0.0001 (0.01%) in gnomAD.
Modification Type:
Disease-specific,Gene-specific,Strength
Not Applicable
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| PM3 | ||||
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Original ACMG Summary
For recessive disorders, detected in trans with a pathogenic variant
Note: This requires testing of parents (or offspring) to determine phase.
VCEP Specifications:
Strength is determined using the ClinGen SVI guidelines (https://clinicalgenome.org/site/assets/files/3717/svi_proposal_for_pm3_criterion_-_version_1.pdf). Both variants must meet PM2_Supporting specification, i.e. be sufficiently rare, unless they are in the exception list (Appendix 4), or present in gnomAD with <20x genomic coverage. Phase is confirmed in trans by testing both or one parent, and the pathogenicity of the variant on the other allele must have at least 2-star rating in ClinVar or VCEP consensus recommendation Stand Alone
Very Strong
For recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient Strength is determined using the ClinGen SVI guidelines.
Modification Type:
Strength
Strong
For recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient. Strength is determined using the ClinGen SVI guidelines.
Modification Type:
Strength
Moderate
For recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient. Strength is determined using the ClinGen SVI guidelines.
Modification Type:
No change
Supporting
For recessive disorders, detected in trans with a pathogenic or likely pathogenic variant in an affected patient. Strength is determined using the ClinGen SVI guidelines.
Modification Type:
Strength
Not Applicable
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| PM4 | ||||
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Original ACMG Summary
Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.
VCEP Specifications:
Relevant for stop codon mutations leading to elongated α-chains (e.g., Hb Constant Spring) and in-frame deletions of a complete codon (leading to deletion of a single amino acid in an otherwise functional haemoglobin variant). Should not be used, if PVS1 has been applied. Stand Alone
Very Strong
Strong
Moderate
Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants.
Modification Type:
No change
Supporting
Not Applicable
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| PM5 | ||||
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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.
VCEP Specifications:
Beware of changes that impact splicing rather than at the amino acid/protein level. Assess potential for creation of exonic splicing event using in silico splicing prediction tools, as described in PP3/BP4. A previously established variant as pathogenic must have at least 2-star rating in ClinVar or VCEP consensus recommendation. Stand Alone
Very Strong
Strong
Moderate
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before, or base change at a non-coding position and previous pathogenic mutation has been seen before. Examples: Arg156His is pathogenic; now you observe Arg156Cys. Non-coding variant g.15300G>C is pathogenic, now you observe g. 15300G>A.
Modification Type:
Disease-specific,Gene-specific
Supporting
Not Applicable
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| PM6 | ||||
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Original ACMG Summary
Assumed de novo, but without confirmation of paternity and maternity.
VCEP Specifications:
In contrast to PS2, identity testing was NOT performed in parental samples to confirm identity, which is assumed. Should not be used in combination with PS2. Stand Alone
Very Strong
Strong
Moderate
Assumed de novo, but without confirmation of paternity and maternity.
Modification Type:
No change
Supporting
Not Applicable
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| PP1 | ||||
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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:
LOD score for recessive disorder can be estimated from the tables in Appendix 1 (Segregation Analysis), based on the number of affected and unaffected individuals. Caution needed when counting segregations in the presence of other possible disease-causing variants. Compound heterozygous individuals are counted only if phase is confirmed to be in trans. Stand Alone
Very Strong
Strong
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. Strong evidence requires LOD score >2.1.
Modification Type:
Disease-specific,Gene-specific,Strength
Moderate
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. MODERATE evidence requires LOD score >1.5.
Modification Type:
Disease-specific,Gene-specific,Strength
Supporting
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. SUPPORTING evidence requires LOD score >0.9.
Modification Type:
Disease-specific,Gene-specific
Not Applicable
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| PP2 | ||||
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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.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
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| PP3 | ||||
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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
Moderate
Supporting
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). For missense: REVEL score > 0.8 OR SpliceAI > 0.3. If REVEL score is not available, use CADD PHRED score > 23.5 For non-coding, synonymous, inframe indels, stop-lost: CADD PHRED score > 12 OR SpliceAI DS > 0.3 Should not be used for LOF variants considered in PVS1.
Modification Type:
Disease-specific,Gene-specific
Not Applicable
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| PP4 | ||||
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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
Moderate
Supporting
Not Applicable
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| PP5 | ||||
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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 | ||||
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Original ACMG Summary
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
VCEP Specifications:
Use the Filtering AF, such as Popmax FAF from gnomAD. If the variant is present at high frequency in the non-continental population (e.g., Ashkenazi Jews), you can calculate the filtering allele frequency using a 95% confidence interval by selecting "Inverse AF" at http://cardiodb.org/allelefrequencyapp/ Assumptions to calculate this threshold: For α-haemoglobinopathies (autosomal recessive):
Variants in Appendix 4 are excluded from this criterion. Stand Alone
Allele frequency ≥0.005 (0.5%) in a studied general population with ≥2000 alleles and variant present in ≥5 alleles.
Modification Type:
Disease-specific,Gene-specific
Very Strong
Strong
Moderate
Supporting
Not Applicable
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| BS1 | ||||
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Original ACMG Summary
Allele frequency is greater than expected for disorder.
VCEP Specifications:
Use the Filtering AF, such as Popmax FAF from gnomAD. If the variant is present at high frequency in the non-continental population (e.g. Ashkenazi Jews), you can calculate the filtering allele frequency using a 95% confidence interval by selecting "Inverse AF" at http://cardiodb.org/allelefrequencyapp/ Assumptions to calculate this threshold: For α-haemoglobinopathies (autosomal recessive):
Variants in Appendix 4 are excluded from this criterion. Stand Alone
Very Strong
Strong
Allele frequency ≥0.001 (0.1%) in a studied general population with ≥2000 alleles and variant present in ≥5 alleles.
Modification Type:
Disease-specific,Gene-specific
Moderate
Supporting
Not Applicable
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| 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:
Normal haematological values are provided in Appendix 3 The healthy individual must be well-phenotyped/well-documented to rule out any mild symptoms and ensure that the individual is unaffected. A full-blood count and Hb characterization are required to exclude variants and/or abnormal quantities. In compound heterozygous individuals, only established pathogenic variants should be considered (i.e. at least 2-star rating in ClinVar). Applies to subjects over 2 years of age. BS2: Only applicable if no coinheritance is detected of an HBB pathogenic variant. BS2_P: Only applicable if no well-established disease-modifying mutations are detected. Stand Alone
Very Strong
Strong
Two independent occurrences in individuals (asymptomatic or with trait phenotype) for a recessive (homozygous or compound heterozygous) disorder, with full penetrance expected at early age.
Modification Type:
Disease-specific,Gene-specific
Moderate
Supporting
Observation in one individual (asymptomatic or with trait phenotype) for a recessive (homozygous or compound heterozygous) disorder, with full penetrance expected at early age.
Modification Type:
Disease-specific,Gene-specific,Strength
Not Applicable
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| BS3 | ||||
|
Original ACMG Summary
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
VCEP Specifications:
The list of approved functional studies can be found in the Appendix 2 (Functional Studies). Stand Alone
Very Strong
Strong
Moderate
Supporting
In vivo or in vitro functional studies show no damaging effect on gene, gene product, expression levels and protein function.
Modification Type:
Disease-specific,Gene-specific,Strength
Not Applicable
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| BS4 | ||||
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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. Stand Alone
Very Strong
Strong
Lack of segregation in affected members of a family.
Modification Type:
No change
Moderate
Supporting
Not Applicable
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| BP1 | ||||
|
Original ACMG Summary
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
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| BP2 | ||||
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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:
Do not use when the variant has only ever been observed in cis with a pathogenic variant as its significance/severity in isolation is unknown. Only applies when the phenotype is not more severe than when either of the two variants are seen in isolation. Use only if in cis with variants classified as pathogenic in ClinVar with at least two-star rating. Stand Alone
Very Strong
Strong
Moderate
Supporting
Observed in cis with a pathogenic variant in any inheritance pattern.
Modification Type:
No change
Not Applicable
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| BP3 | ||||
|
Original ACMG Summary
In frame-deletions/insertions in a repetitive region without a known function.
Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
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| 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
Moderate
Supporting
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) For missense: REVEL score < 0.7 AND SpliceAI DS ≤ 0.3 (if REVEL score is not available, use CADD PHRED score ≤ 20, instead) For non-coding, synonymous, inframe indels, stop-lost: CADD PHRED score ≤ 11 AND SpliceAI DS ≤ 0.3
Modification Type:
Disease-specific,Gene-specific
Not Applicable
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| BP5 | ||||
|
Original ACMG Summary
Variant found in a case with an alternate molecular basis for disease.
VCEP Specifications:
This is about phenotypes that are COMPLETELY explained by variants in different genes. Stand Alone
Very Strong
Strong
Moderate
Supporting
Not Applicable
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| 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
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| BP7 | ||||
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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:
Synonymous variant with no impact on splicing (SpliceAI ≤0.3) AND GERP++ <0 for conservation. Stand Alone
Very Strong
Strong
Moderate
Supporting
A synonymous (silent) 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.
Modification Type:
No change
Not Applicable
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