rs1057524804
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_000719.7(CACNA1C):c.1917C>A(p.Asn639Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,417,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Synonymous variant affecting the same amino acid position (i.e. N639N) has been classified as Likely benign.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.1917C>A | p.Asn639Lys | missense_variant | 14/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.1917C>A | p.Asn639Lys | missense_variant | 14/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.1917C>A | p.Asn639Lys | missense_variant | 14/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.1917C>A | p.Asn639Lys | missense_variant | 14/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 29
GnomAD4 exome AF: 7.05e-7 AC: 1AN: 1417586Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 700684
GnomAD4 genome ? Cov.: 29
ClinVar
Submissions by phenotype
Timothy syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Feb 02, 2018 | - - |
Congenital long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 02, 2020 | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to lysine (exon 14). (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). Note: this region has <30x coverage. (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. Moderate amino acid change, very high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. Located in the intracellular region between subunits S4 and S5 of Domain II (PMID: 31004778). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. PMID: 31004778; p.(Asn639Thr) considered likely pathogenic in a female proband, her brother and mother with prolonged QT/?Timothy syndrome. Functional studies of CRISPR/Cas9-edited hiPSC-CMs had indicated an impact on the channel (increased action potential and slower voltage-dependent inactivation). (SP) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: VUS x1 (condition: Timothy syndrome) with an alternative nucleotide change (C>G) causing the same amino acid change also reported as a VUS x2 in ClinVar (conditions: Timothy syndrome, Not provided). (I) 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 - |
Long QT syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 30, 2020 | This sequence change replaces asparagine with lysine at codon 639 of the CACNA1C protein (p.Asn639Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 560694). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at