rs375320117
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001232.4(CASQ2):c.1015-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000275 in 1,597,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001232.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASQ2 | NM_001232.4 | c.1015-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000261448.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASQ2 | ENST00000261448.6 | c.1015-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001232.4 | P1 | |||
CASQ2 | ENST00000488931.2 | c.*387-3C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000360 AC: 9AN: 250178Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135168
GnomAD4 exome AF: 0.0000228 AC: 33AN: 1445244Hom.: 0 Cov.: 29 AF XY: 0.0000208 AC XY: 15AN XY: 720054
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74332
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 16, 2021 | This sequence change falls in intron 10 of the CASQ2 gene. It does not directly change the encoded amino acid sequence of the CASQ2 protein. It affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs375320117, ExAC 0.008%). This variant has not been reported in the literature in individuals with CASQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 238668). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2020 | The c.1015-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 11 in the CASQ2 gene. This nucleotide position is not well conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by ESEfinder to weaken the efficiency of the native splice acceptor site, but is not predicted to have a deleterious effect on this splice acceptor/donor site by BDGP; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 26, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at