rs756829999
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_000719.7(CACNA1C):c.5339G>A(p.Arg1780His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000719.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.5339G>A | p.Arg1780His | missense_variant | 42/47 | ENST00000399655.6 | NP_000710.5 | |
CACNA1C | NM_001167623.2 | c.5339G>A | p.Arg1780His | missense_variant | 42/47 | ENST00000399603.6 | NP_001161095.1 | |
CACNA1C-AS1 | NR_045725.1 | n.334-1794C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.5339G>A | p.Arg1780His | missense_variant | 42/47 | 5 | NM_001167623.2 | ENSP00000382512 | ||
CACNA1C | ENST00000399655.6 | c.5339G>A | p.Arg1780His | missense_variant | 42/47 | 1 | NM_000719.7 | ENSP00000382563 | ||
CACNA1C-AS1 | ENST00000501371.5 | n.295-1794C>T | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 242558Hom.: 0 AF XY: 0.0000152 AC XY: 2AN XY: 131948
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1459866Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6AN XY: 726072
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74318
ClinVar
Submissions by phenotype
CACNA1C-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 16, 2022 | The CACNA1C c.5339G>A variant is predicted to result in the amino acid substitution p.Arg1780His. This variant has been reported in the heterozygous state in a 57 year old asymptomatic male but diagnosed with Brugada syndrome (saddle-back type) pattern ECG at an annual health check-up (Case 4, Fukuyama et al. 2013. PubMed ID: 23575362). This variant has also been reported in a registry of variants associated with Brugada syndrome (Supplementary Table 1, Chen et al. 2019. PubMed ID: 30662450) and was reported as a variant of uncertain significance in a study of genetics associated with Brugada syndrome (Campuzano et al. 2019. PubMed ID: 30821013). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-2788857-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 18, 2019 | The p.R1780H variant (also known as c.5339G>A), located in coding exon 42 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5339. The arginine at codon 1780 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in a Japanese cohort in an individual with Brugada syndrome sign on ECG; however, the patient was asymptomatic and family history information was not available (Fukuyama M et al. Circ. J., 2013 Apr;77:1799-806). This amino acid position is poorly conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Long QT syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 02, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at