chr17-80104910-T-C
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145781/MONDO:0009290/010
Frequency
Consequence
NM_000152.5 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.722 AC: 109760AN: 152070Hom.: 39921 Cov.: 34
GnomAD3 exomes AF: 0.723 AC: 178297AN: 246688Hom.: 65703 AF XY: 0.738 AC XY: 98988AN XY: 134130
GnomAD4 exome AF: 0.743 AC: 1084167AN: 1459628Hom.: 404400 Cov.: 80 AF XY: 0.746 AC XY: 541839AN XY: 726082
GnomAD4 genome AF: 0.722 AC: 109824AN: 152188Hom.: 39941 Cov.: 34 AF XY: 0.721 AC XY: 53629AN XY: 74414
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Benign:7
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The highest continental population minor allele frequency for c.324T>C (p.Cys108=) in gnomAD v2.1.1 is 0.81776 in the South Asian population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92484, two star review status), with 10 submitters classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -
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not specified Benign:6
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p.Cys108Cys in exon 3 of GAA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 82% (13463/16390) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs1800300). -
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not provided Uncertain:1Benign:4
Variant summary: The GAA c.324T>C (p.Cys108Cys) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 86202/117014 control chromosomes (32095 homozygotes) at a frequency of 0.7366811, indicating the C allele is the major allele. This frequency is approximately 175 times the estimated maximal expected allele frequency of a pathogenic GAA variant (0.0042205), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant has been classified as benign. -
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multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 82.142% in ExAC) based on the frequency threshold of 2.76% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.A synonymous variant not located in a splice region. -
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Primary ciliary dyskinesia Benign:1
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Cardiovascular phenotype Benign:1
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at