rs397517264
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBS1_SupportingBS2
The NM_016203.4(PRKAG2):c.1390G>A(p.Asp464Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_016203.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.1390G>A | p.Asp464Asn | missense_variant | Exon 12 of 16 | ENST00000287878.9 | NP_057287.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135914
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461478Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727064
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 6 Uncertain:3
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
This variant has been identified as part of our research program. The variant was identified in 1 HCM proband of Lebanese descent who was tested at Blueprint Genetics. For further information please feel free to contact us. -
- -
not specified Uncertain:2
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp464Asn variant in PRKAG2 has been identified by our laboratory in 1 Lebanese individua l with LVNC and WPW and segregated with disease in 1 affected relative. This var iant has been identified in 5/66738 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397517264). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In addition, this variant is located wit hin the CBS domain region where all pathogenic PRKAG2 variants have been identif ied to date (Oliveira 2003). In summary, while there is some suspicion for a pat hogenic role, the clinical significance of the p.Asp464Asn variant is uncertain. -
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Asp464Asn (c. 1390 G>A) in PRKAG2 This variant is novel. This results in a non-conservative amino acid change, where a negatively-charged amino acid (Aspartic Acid) is changed to a neutral, polar amino acid (Asparagine). This variant is predicted to be benign by PolyPhen-2 analysis. This residue is conserved across species. No other disease-causing variants have been reported at this or nearby codons. The variant was not observed in 313 individuals of various ethnic backgrounds at GeneDx. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~5,000 Caucasian and African American individuals (as of May 2012). The variant is not listed in dbSNP or 1000 genomes (as of May 2012). -
Cardiomyopathy Uncertain:2
This missense variant replaces aspartic acid with asparagine at codon 464 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (ClinVar: SCV001156311.1, SCV001468149.1, SCV000264153.2) or dilated cardiomyopathy (PMID: 33029862). This variant has also been reported in two related individuals affected with left ventricular noncompaction cardiomyopathy and Wolff-Parkinson-White syndrome (ClinVar: SCV000062594.5). This variant has been identified in 8/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
- -
not provided Uncertain:2
The PRKAG2 c.1390G>A; p.Asp464Asn variant (rs397517264, ClinVar Variation ID: 45697) is reported in the literature in two individuals affected with dilated cardiomyopathy (DCM) and one individual affected with primary electrical disease (Perret 2024, Proost 2017, VanDyke 2021). This variant is found in the non-Finnish European population with an allele frequency of 0.007% (8/113758 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.506). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Perret C et al. DNA-pools targeted-sequencing as a robust cost-effective method to detect rare variants: Application to dilated cardiomyopathy genetic diagnosis. Clin Genet. 2024 Feb;105(2):185-189. PMID: 37904629. Proost D et al. Targeted Next-Generation Sequencing of 51 Genes Involved in Primary Electrical Disease. J Mol Diagn. 2017 May;19(3):445-459. PMID: 28341588. VanDyke RE et al. Impact of variant reclassification in the clinical setting of cardiovascular genetics. J Genet Couns. 2021 Apr;30(2):503-512. PMID: 33029862. -
Reported in ClinVar as a variant of uncertain significance by several laboratories; one laboratory identified this variant in 1 Lebanese individual with LVNC and Wolff-Parkinson-White syndrome, and the variant segregated with disease in 1 affected relative (SCV000062594.4; ClinVar Variant ID# 45697; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28341588) -
Wolff-Parkinson-White pattern Uncertain:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hypertrophic cardiomyopathy Uncertain:1
This missense variant replaces aspartic acid with asparagine at codon 464 of the PRKAG2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (ClinVar: SCV001156311.1, SCV001468149.1, SCV000264153.2) or dilated cardiomyopathy (PMID: 33029862). This variant has also been reported in two related individuals affected with left ventricular noncompaction cardiomyopathy and Wolff-Parkinson-White syndrome (ClinVar: SCV000062594.5). This variant has been identified in 8/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Primary familial hypertrophic cardiomyopathy Uncertain:1
- -
Cardiovascular phenotype Uncertain:1
The p.D464N variant (also known as c.1390G>A), located in coding exon 12 of the PRKAG2 gene, results from a G to A substitution at nucleotide position 1390. The aspartic acid at codon 464 is replaced by asparagine, an amino acid with highly similar properties. This variant was detected in one individual from a primary electrical disease cohort, who had additional cardiac variants also reported (Proost D et al. J Mol Diagn, 2017 05;19:445-459). This alteration has also been reported in association with dilated cardiomyopathy (DCM) (VanDyke RE et al. J Genet Couns, 2021 Apr;30:503-512; Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is highly 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 Uncertain:1
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 464 of the PRKAG2 protein (p.Asp464Asn). This variant is present in population databases (rs397517264, gnomAD 0.007%). This missense change has been observed in individual(s) with arrhythmogenic cardiomyopathy and/or dilated cardiomyopathy (PMID: 33029862; internal data). ClinVar contains an entry for this variant (Variation ID: 45697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PRKAG2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at