chr7-151576452-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2
The NM_016203.4(PRKAG2):c.865G>A(p.Val289Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000347 in 1,439,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_016203.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.865G>A | p.Val289Ile | missense_variant, splice_region_variant | Exon 7 of 16 | ENST00000287878.9 | NP_057287.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250708Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135514
GnomAD4 exome AF: 0.00000347 AC: 5AN: 1439194Hom.: 0 Cov.: 30 AF XY: 0.00000558 AC XY: 4AN XY: 717358
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
The Val289Ile variant in PRKAG2 has not been reported in the literature and was absent from in large European American and African American populations by the N HLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS), which increase s the likelihood that the variant is pathogenic. This variant has been identifie d by our laboratory in 1 Caucasian individual with HCM who also carried a pathog enic MYBPC3 variant. The variant occurs in the first base of the exon and though variants in this position can sometimes affect splicing, computational tools do not predict an effect. Valine (Val) at position 289 is highly conserved in mamm als and across evolutionarily distant species, though computational analyses (bi ochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional i nformation is needed to fully assess the clinical significance of this variant. -
Cardiomyopathy Uncertain:1
This missense variant replaces valine with isoleucine at codon 289 of the PRKAG2 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/250708 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:1
Identified in a patient with hypertrophic cardiomyopathy, but additional clinical information was not included (Walsh R et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257) -
Wolff-Parkinson-White pattern;C1833236:Hypertrophic cardiomyopathy 6;C1849813:Lethal congenital glycogen storage disease of heart Uncertain:1
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Hypertrophic cardiomyopathy Uncertain:1
This missense variant replaces valine with isoleucine at codon 289 of the PRKAG2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 1/250708 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. -
Lethal congenital glycogen storage disease of heart Uncertain:1
This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 289 of the PRKAG2 protein (p.Val289Ile). This variant is present in population databases (rs397517282, gnomAD 0.0009%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 45736). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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