rs1555968941
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000719.7(CACNA1C):c.4087G>A(p.Val1363Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V1363L) has been classified as Pathogenic.
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.4087G>A | p.Val1363Met | missense_variant | 33/47 | ENST00000399655.6 | |
CACNA1C | NM_001167623.2 | c.4087G>A | p.Val1363Met | missense_variant | 33/47 | ENST00000399603.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.4087G>A | p.Val1363Met | missense_variant | 33/47 | 5 | NM_001167623.2 | ||
CACNA1C | ENST00000399655.6 | c.4087G>A | p.Val1363Met | missense_variant | 33/47 | 1 | NM_000719.7 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2017 | The V1363M variant in the CACNA1C gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V1363M variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1363M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret V1363M as a likely pathogenic variant. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 14, 2022 | - - |
CACNA1C-related disorder Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Likely pathogenic and reported on 07/24/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at