rs397517270
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2
The NM_016203.4(PRKAG2):c.425C>T(p.Thr142Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,613,994 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).
Frequency
Consequence
NM_016203.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PRKAG2 | NM_016203.4 | c.425C>T | p.Thr142Ile | missense_variant | Exon 3 of 16 | ENST00000287878.9 | NP_057287.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000716 AC: 18AN: 251296Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135808
GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461768Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46AN XY: 727164
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
This missense variant replaces threonine with isoleucine at codon 142 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 (PMID: 27532257, 30847666), left ventricular noncompaction (PMID: 28798025), possible arrhythmogenic right ventricular cardiomyopathy (PMID: 29253866), or long QT syndrome (PMID: 33876311). This variant has also been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 35588295), including one de novo report (PMID: 35588295). This variant has also been identified in 20/282698 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 T142I variant has been reported previously in association with dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) (Pugh et al., 2014; Miszalski-Jamka et al., 2017; Walsh et al.., 2017). Pugh et al. (2014) reported T142I as a variant of uncertain significance in one patient who was diagnosed with sporadic DCM. Subsequently, T142I was reported in a patient with LVNC who underwent whole exome sequencing (WES) who also harbored a variant in the ABCC6 gene (Miszalski-Jamka et al., 2017). In addition, the T142I variant has been classified as a variant of uncertain significance by several other clinical laboratories in ClinVar (SCV000062617.5; SCV000290210.2; SCV000290210.2; Landrum et al., 2016). The T142I variant is a non-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Lastly, the T142I variant was observed in 0.0197% (2/10152) of alleles from individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek et al., 2016). -
Hypertrophic cardiomyopathy Uncertain:2
- -
This missense variant replaces threonine with isoleucine at codon 142 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 (PMID: 27532257, 30847666), left ventricular noncompaction (PMID: 28798025), possible arrhythmogenic right ventricular cardiomyopathy (PMID: 29253866), or long QT syndrome (PMID: 33876311). This variant has also been reported in individuals affected with dilated cardiomyopathy (PMID: 24503780, 27532257, 35588295), including one de novo report (PMID: 35588295). This variant has also been identified in 20/282698 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 specified Uncertain:1
The Thr142Ile variant has not been reported in the literature. However, this var iant has been identified by our laboratory in one individual with a second, like ly pathogenic mutation and in another individual with a clinical diagnosis of d ilated cardiomyopathy (DCM); PRKAG2 variants are more commonly associated with HCM/LVH and WPW (Oliveira, 2003). In addition, the Thr80Asn variant is located outside the CBS domain region where all pathogenic PRKAG2 variants have been id entified to date. In summary, while these observations suggest that this could be a benign variant, its clinical significance cannot be determined with certain ty at this time. -
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. -
Arrhythmogenic right ventricular dysplasia 9 Uncertain:1
- -
Wolff-Parkinson-White pattern;C1833236:Hypertrophic cardiomyopathy 6;C1849813:Lethal congenital glycogen storage disease of heart Uncertain:1
- -
Hypertrophic cardiomyopathy 6 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. -
Cardiovascular phenotype Uncertain:1
The c.425C>T (p.T142I) alteration is located in exon 3 (coding exon 3) of the PRKAG2 gene. This alteration results from a C to T substitution at nucleotide position 425, causing the threonine (T) at amino acid position 142 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Lethal congenital glycogen storage disease of heart Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at