rs750835733
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_ModeratePM1PM2PM5PP2PP3PP5_Moderate
The NM_000719.7(CACNA1C):c.2570C>G(p.Pro857Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,430 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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P857A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.2570C>G | p.Pro857Arg | missense_variant | 19/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.2570C>G | p.Pro857Arg | missense_variant | 19/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.2570C>G | p.Pro857Arg | missense_variant | 19/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.2570C>G | p.Pro857Arg | missense_variant | 19/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248512Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134800
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461430Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726944
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Long qt syndrome 8 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 05, 2019 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2021 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 23677916). 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 633643). This missense change has been observed in individuals with long QT syndrome (PMID: 23677916, 32161207; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs750835733, gnomAD 0.003%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 857 of the CACNA1C protein (p.Pro857Arg). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at