rs148056866
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_016203.4(PRKAG2):c.521C>T(p.Thr174Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000452 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T174A) has been classified as Uncertain significance.
Frequency
Consequence
NM_016203.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.521C>T | p.Thr174Met | missense_variant | 4/16 | ENST00000287878.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PRKAG2 | ENST00000287878.9 | c.521C>T | p.Thr174Met | missense_variant | 4/16 | 1 | NM_016203.4 | P3 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135918
GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461818Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 727216
GnomAD4 genome AF: 0.000184 AC: 28AN: 152328Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74484
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 164991; Landrum et al., 2016) - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 03, 2017 | - - |
Cardiomyopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 30, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 24, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 31, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Thr174Met varia nt in PRKAG2 has not been reported in individuals with cardiomyopathy, but has b een identified in 0.5% (1/192) of Kenyan chromosomes by the 1000 Genomes Project and in 3/4406 African American chromosomes by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS/; dbSNP rs148056866). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIF T) suggest that the Thr174Met variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. Although this data supports that the Thr174Met variant may be benign, additional studies are neede d to fully assess its clinical significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2023 | The p.T174M variant (also known as c.521C>T), located in coding exon 4 of the PRKAG2 gene, results from a C to T substitution at nucleotide position 521. The threonine at codon 174 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in cardiac genetic testing cohorts; however, clinical details were limited and additional cardiac variants were detected in some cases (Seidelmann SB et al. Circ Cardiovasc Genet, 2017 Feb;10:[ePub ahead of print]; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309; Pottinger TD et al. J Am Heart Assoc, 2020 02;9:e013808). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Lethal congenital glycogen storage disease of heart Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at