1-115701291-T-TATC
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001232.4(CASQ2):c.1147_1149dupGAT(p.Asp383dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,594,326 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001232.4 conservative_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASQ2 | ENST00000261448.6 | c.1147_1149dupGAT | p.Asp383dup | conservative_inframe_insertion | Exon 11 of 11 | 1 | NM_001232.4 | ENSP00000261448.5 | ||
CASQ2 | ENST00000488931.2 | n.*519_*521dupGAT | non_coding_transcript_exon_variant | Exon 13 of 13 | 3 | ENSP00000518226.1 | ||||
CASQ2 | ENST00000488931.2 | n.*519_*521dupGAT | 3_prime_UTR_variant | Exon 13 of 13 | 3 | ENSP00000518226.1 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152086Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000560 AC: 14AN: 250136Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135164
GnomAD4 exome AF: 0.0000485 AC: 70AN: 1442122Hom.: 1 Cov.: 26 AF XY: 0.0000473 AC XY: 34AN XY: 718686
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74404
ClinVar
Submissions by phenotype
not provided Uncertain:2
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Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In-frame duplication of 1 amino acids in a repetitive region with no known function -
not specified Uncertain:1
The Asp378[7] variant in CASQ2 has not been previously reported in individuals w ith cardiomyopathy. Data from large population studies is insufficient to assess the frequency of this variant. This variant results in the addition of a single aspartic acid (Asp) in a poly aspartic acid stretch, which does not alter the r emainder of the protein. It is unclear if this addition impacts the protein. A d eletion (Asp378[5]) in this same string of residues has been identified by our l aboratory in 2 individuals with HCM, one of whom carried a likely pathogenic var iant in another gene (LMM unpublished data) and is listed in dbSNP (rs72554069) with limited frequency information. At this time, additional information is need ed to fully assess the clinical significance of the Asp378[7] variant. -
Cardiomyopathy Uncertain:1
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Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1
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Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
This variant, c.1147_1149dup, results in the insertion of 1 amino acid(s) of the CASQ2 protein (p.Asp383dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179599). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at