chr12-2691124-G-A
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000719.7(CACNA1C):c.6342G>A(p.Ala2114=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000503 in 1,609,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
CACNA1C
NM_000719.7 synonymous
NM_000719.7 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.28
Genes affected
CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.67).
BP6
Variant 12-2691124-G-A is Benign according to our data. Variant chr12-2691124-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 383377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2691124-G-A is described in Lovd as [Benign]. Variant chr12-2691124-G-A is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=1.28 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000985 (15/152246) while in subpopulation EAS AF= 0.00174 (9/5158). AF 95% confidence interval is 0.00091. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 15 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1C | NM_000719.7 | c.6342G>A | p.Ala2114= | synonymous_variant | 47/47 | ENST00000399655.6 | NP_000710.5 | |
CACNA1C | NM_001167623.2 | c.6342G>A | p.Ala2114= | synonymous_variant | 47/47 | ENST00000399603.6 | NP_001161095.1 | |
CACNA1C-AS1 | NR_045725.1 | n.34C>T | non_coding_transcript_exon_variant | 1/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1C | ENST00000399603.6 | c.6342G>A | p.Ala2114= | synonymous_variant | 47/47 | 5 | NM_001167623.2 | ENSP00000382512 | ||
CACNA1C | ENST00000399655.6 | c.6342G>A | p.Ala2114= | synonymous_variant | 47/47 | 1 | NM_000719.7 | ENSP00000382563 | ||
CACNA1C-AS1 | ENST00000501371.5 | upstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152128Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000102 AC: 25AN: 244882Hom.: 0 AF XY: 0.0000823 AC XY: 11AN XY: 133624
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GnomAD4 exome AF: 0.0000453 AC: 66AN: 1456924Hom.: 0 Cov.: 31 AF XY: 0.0000387 AC XY: 28AN XY: 723898
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GnomAD4 genome AF: 0.0000985 AC: 15AN: 152246Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74448
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:1
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Long QT syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2017 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at