12-2567682-G-A
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2
The NM_000719.7(CACNA1C):c.1783G>A(p.Val595Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,613,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V595V) has been classified as Likely benign.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.1783G>A | p.Val595Ile | missense_variant | 13/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.1783G>A | p.Val595Ile | missense_variant | 13/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.1783G>A | p.Val595Ile | missense_variant | 13/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.1783G>A | p.Val595Ile | missense_variant | 13/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000177 AC: 44AN: 249014Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 134996
GnomAD4 exome AF: 0.000103 AC: 150AN: 1461386Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74AN XY: 726944
GnomAD4 genome AF: 0.000177 AC: 27AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17AN XY: 74444
ClinVar
Submissions by phenotype
CACNA1C-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 14, 2024 | The CACNA1C c.1783G>A variant is predicted to result in the amino acid substitution p.Val595Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.088% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2019 | Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance and a likely benign variant (ClinVar Variant ID 190611; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2019 | 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