NM_001232.4:c.546delT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001232.4(CASQ2):c.546delT(p.Phe182LeufsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,230 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001232.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASQ2 | ENST00000261448.6 | c.546delT | p.Phe182LeufsTer28 | frameshift_variant | Exon 5 of 11 | 1 | NM_001232.4 | ENSP00000261448.5 | ||
CASQ2 | ENST00000488931.2 | n.270delT | non_coding_transcript_exon_variant | Exon 6 of 13 | 3 | ENSP00000518226.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251264Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135796
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461142Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 726928
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 2 Pathogenic:3
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with catecholaminergic polymorphic ventricular tachycardia 2 (MIM#611938). (I) 0108 - This gene is associated with both recessive and dominant disease. There is definitive evidence for autosomal recessive CPVT and moderate evidence for autosomal dominant CPVT (ClinGen). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported as pathogenic or likely pathogenic in many individuals with CPVT (ClinVar, PMID: 32693635). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported in a compound heterozygous state in a seven-year-old with CPVT. The proband’s carrier mother also had emotion-induced syncope and exercise-induced ventricular bigeminy at age 68 (PMID: 21618644, 32693635). This variant has a likely pathogenic entry in ClinVar for CPVT and has been identified in a SIDS individual however, the zygosity of the variant was not provided in either case (PMID: 29544605). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:2
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This sequence change creates a premature translational stop signal (p.Phe182Leufs*28) in the CASQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). This variant is present in population databases (rs763955301, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (PMID: 19398665, 21618644, 29544605, 32693635). ClinVar contains an entry for this variant (Variation ID: 222522). For these reasons, this variant has been classified as Pathogenic. -
Cardiovascular phenotype Pathogenic:1
The c.546delT pathogenic mutation, located in coding exon 5 of the CASQ2 gene, results from a deletion of one nucleotide at nucleotide position 546, causing a translational frameshift with a predicted alternate stop codon (p.F182Lfs*28). This variant co-occurred in trans with a second CASQ2 variant in a proband reported to have catecholaminergic polymorphic ventricular tachycardia (CPVT) (Roux-Buisson N et al. Hum Mutat, 2011 Sep;32:995-9). This variant has also been detected in a case of sudden infant death and an additional CVPT cohort; however, details were limited (Tester DJ et al. J Am Coll Cardiol, 2018 Mar;71:1217-1227). (Ng K et al. Circulation, 2020 Sep;142:932-947). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at