rs28938173
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_016203.4(PRKAG2):c.1199C>A(p.Thr400Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T400A) has been classified as Uncertain significance.
Frequency
Consequence
NM_016203.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.1199C>A | p.Thr400Asn | missense_variant | 11/16 | ENST00000287878.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKAG2 | ENST00000287878.9 | c.1199C>A | p.Thr400Asn | missense_variant | 11/16 | 1 | NM_016203.4 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
PRKAG2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 04, 2023 | The PRKAG2 c.1199C>A variant is predicted to result in the amino acid substitution p.Thr400Asn. This variant has been reported in an individual with cardiac hypertrophy (Family SS, Arad et al 2002. PubMed ID: 11827995). While in vitro functional studies expressing this variant in CCL13 cells could not show evidence of constitutive activation of AMP kinase when compared to wild-type (Scott JW et al. 2004. PubMed ID: 14722619), in vivo functional studies in transgenic mice demonstrate that the mice showed significantly increased cardiac mass/body mass ratios and led to cardiac hypertrophy by inappropriate activation of AMP kinase and glycogen deposition (Banerjee et al. 2010. PubMed ID: 20005292; Ramratnam et al. 2014. PubMed ID: 25092788; Banerjee et al 2007. PubMed ID: 17597581). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. - |
Hypertrophic cardiomyopathy 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2002 | - - |
Hypertrophic cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 03, 2018 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at