rs56180838

Positions:

• chr12-2651732-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000719.7(CACNA1C):​c.4038C>T​(p.Ile1346=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,613,286 control chromosomes in the GnomAD database, including 3,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (205 hom., cov: 31)
  • Exomes 𝑓: 0.059 (2948 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.16

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 12-2651732-C-T is Benign according to our data. Variant chr12-2651732-C-T is described in ClinVar as [Benign]. Clinvar id is 136623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2651732-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.16 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.4038C>T	p.Ile1346=	synonymous_variant	32/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.4038C>T	p.Ile1346=	synonymous_variant	32/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4038C>T	p.Ile1346=	synonymous_variant	32/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.4038C>T	p.Ile1346=	synonymous_variant	32/47	1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.0447 AC: 6792 AN: 152058 Hom.: 205 Cov.: 31

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.0545

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0152

Gnomad FIN AF: 0.0807

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.0484

GnomAD3 exomes AF: 0.0477 AC: 11844 AN: 248480 Hom.: 418 AF XY: 0.0486 AC XY: 6546 AN XY: 134738

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.0277

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.000222

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0826

Gnomad NFE exome AF: 0.0672

Gnomad OTH exome AF: 0.0542

GnomAD4 exome AF: 0.0594 AC: 86756 AN: 1461110 Hom.: 2948 Cov.: 33 AF XY: 0.0583 AC XY: 42369 AN XY: 726786

Gnomad4 AFR exome AF: 0.00854

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.0510

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0859

Gnomad4 NFE exome AF: 0.0668

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.0446 AC: 6792 AN: 152176 Hom.: 205 Cov.: 31 AF XY: 0.0445 AC XY: 3314 AN XY: 74394

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0377

Gnomad4 ASJ AF: 0.0545

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0154

Gnomad4 FIN AF: 0.0807

Gnomad4 NFE AF: 0.0660

Gnomad4 OTH AF: 0.0479

Alfa AF: 0.0560 Hom.: 154

Bravo AF: 0.0394

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0644

EpiControl AF: 0.0662

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	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. -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2015

This alteration is classified as 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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56180838; hg19: chr12-2760898; COSMIC: COSV59779215;