rs146664754
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2
The NM_001232.4(CASQ2):āc.567C>Gā(p.Phe189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000752 in 1,613,870 control chromosomes in the GnomAD database, including 3 homozygotes. 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_001232.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000532 AC: 81AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000716 AC: 180AN: 251354Hom.: 0 AF XY: 0.000721 AC XY: 98AN XY: 135842
GnomAD4 exome AF: 0.000775 AC: 1132AN: 1461586Hom.: 3 Cov.: 30 AF XY: 0.000763 AC XY: 555AN XY: 727120
GnomAD4 genome AF: 0.000532 AC: 81AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000578 AC XY: 43AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
- -
- -
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22198169, 24025405, 21618644, 22421959, 21454795, 23022705, 27538377, 21063088, 28818208, 28404607, 34426522, 25651173, 26671417, 18543230, 37937776) -
CASQ2: PM2:Supporting -
- -
Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:4
- -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
- -
- -
not specified Uncertain:1Benign:1
The Phe189Leu variant in CASQ2 has been reported in the heterozygous state in 1 individual with CPVT (Liu 2008). This variant is present at low frequency in var ious large populations, for example in 0.1% (9/8600) of European American chromo somes screened by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs146664754). Studies have shown that the Phe189Leu variant may i mpactthe protein (Eckey 2010). However, this in vitro assay may not accurately r epresent biological function. Computational analyses (biochemical amino acid pro perties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Phe189Le u variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, the available information for this va riant is somewhat conflicting. Additional information is needed to fully assess its clinical significance. -
Variant summary: CASQ2 c.567C>G (p.Phe189Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00075 in 1613870 control chromosomes, predominantly at a frequency of 0.0082 within the Ashkenazi Jewish subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASQ2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016). To our knowledge, no experimental evidence demonstrating this variants impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 162814). Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Uncertain:1Benign:1
- -
- -
Polymorphic ventricular tachycardia Uncertain:1
- -
Sudden unexplained death Benign:1
The CASQ2 Phe189Leu variant has been previously reported in 2 CPVT families (Liu QQ, et al, 2008) and one sudden death case (Rajagopalan A & Pollanen MS, 2016). An in vitro functional study performed on Xenopus oocytes, has shown that the variant causes a reduction in hERG function and reduces flexbility of the CASQ2 protein, which suggests it may play a role in the aetiology of CPVT (Eckey K, et al., 2010). However, the use of an in vitro assay on amphibian oocytes may not reflect the actual biological function of the mutated protein in the mammalian heart. The CASQ2 Phe189Leu variant is present in the Exome Aggregation Consortium dataset (MAF= 0.0007, http://exac.broadinstitute.org/) and is particularly common in the European population; allele frequency=0.091, which is higher then expected for an inherited heart condition. We identified this variant in a case of sudden unexplained death in a young male. Genetic testing in this individual also identified two other variants (NEBL Gln682* & PKP2 Glu85Metfs*260), both of which are very rare. Furthermore, one study identified a substantial overrepresentation of CPVT-associated variants in an exome population database (ESP), the authors predict that these variants are not the monogenic cause of CPVT (Jabbari J, et al, 2013). In summary, based on the high allele frequency in the general population and lack of established functional data in mammalian models or other strong data supportive of a pathogenic role, we classify CASQ2 Phe189Leu as "likely benign". -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
- -
Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
CASQ2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at