rs121908216
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.4979G>A(p.Arg1660His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,470 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1660C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.4979G>A | p.Arg1660His | missense_variant | 32/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.4979G>A | p.Arg1660His | missense_variant | 32/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461470Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727028
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 16, 2021 | DNA sequence analysis of the CACNA1A gene demonstrated a sequence change, c.4982G>A, in exon 32 that results in an amino acid change, p.Arg1661His. This sequence change has not been described in the gnomAD general population database. This sequence change has been described in a family with episodic ataxia type 2 and familial hemiplegic migraine, and was shown to co-segregate with the disease phenotype (PMID: 10987655). The p.Arg1661His change affects a highly conserved amino acid residue located in the S4 transmembrane segment of domain IV of the CACNA1A protein. It appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggests this p.Arg1661His variant is likely pathogenic, however functional studies have not been performed to prove this conclusively. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16325861, 11179022, 11814735, 26814174, 28742085, 34507393, 29482223, 34758253, 10987655, 35401678, 34806130) - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Feb 01, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 14, 2022 | This variant segregates with episodic ataxia in one family (PMID: 10987655) and is also reported in an unrelated individual with pure cerebellar ataxia (PMID: 29482223). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Arg1666His or Arg1660His. Computational tools predict that this variant is damaging. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CACNA1A: PP1:Strong, PM1, PM2, PS4:Moderate, PP2 - |
Episodic ataxia type 2 Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1999 | - - |
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Likely pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 23, 2018 | - - |
Spinocerebellar ataxia type 6 Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | O&I group, Department of Genetics, University Medical Center of Groningen | Jul 22, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 06, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1661 of the CACNA1A protein (p.Arg1661His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of, or diagnosis of, episodic ataxia (PMID: 10987655, 29482223). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg1666His. ClinVar contains an entry for this variant (Variation ID: 8495). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at