rs758390382
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000152.5(GAA):c.2320G>A(p.Asp774Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000825 in 1,612,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000152.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAA | NM_000152.5 | c.2320G>A | p.Asp774Asn | missense_variant | 16/20 | ENST00000302262.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAA | ENST00000302262.8 | c.2320G>A | p.Asp774Asn | missense_variant | 16/20 | 1 | NM_000152.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000803 AC: 20AN: 248994Hom.: 1 AF XY: 0.0000740 AC XY: 10AN XY: 135114
GnomAD4 exome AF: 0.0000753 AC: 110AN: 1460484Hom.: 0 Cov.: 31 AF XY: 0.0000688 AC XY: 50AN XY: 726552
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16AN XY: 74364
ClinVar
Submissions by phenotype
Glycogen storage disease, type II Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2022 | Variant summary: GAA c.2320G>A (p.Asp774Asn) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 248994 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) (8e-05 vs 0.0042), allowing no conclusion about variant significance. c.2320G>A has been reported in the literature in at-least one individual affected with late onset features of Glycogen Storage Disease, Type 2 (Pompe Disease) (example, Musumeci_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed with a pathogenic variant in a patient with late-onset glycogen storage disease type II in published literature (Musumeci et al., 2012), however segregation data was not included; This variant is associated with the following publications: (PMID: 22958975) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at