rs72552065

chr12-2679644-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000719.7(CACNA1C):c.5292C>T(p.Asn1764=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0557 in 1,613,704 control chromosomes in the GnomAD database, including 2,891 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (192 hom., cov: 33)
  • Exomes 𝑓: 0.057 (2699 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.630

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]

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 12-2679644-C-T is Benign according to our data. Variant chr12-2679644-C-T is described in ClinVar as [Benign]. Clinvar id is 136633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2679644-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.5292C>T	p.Asn1764=	synonymous_variant	42/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.5292C>T	p.Asn1764=	synonymous_variant	42/47	ENST00000399603.6
CACNA1C-AS1	NR_045725.1	n.334-1747G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5292C>T	p.Asn1764=	synonymous_variant	42/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.5292C>T	p.Asn1764=	synonymous_variant	42/47	1	NM_000719.7
CACNA1C-AS1	ENST00000501371.5	n.295-1747G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0440 AC: 6702 AN: 152204 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0494

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0650

Gnomad OTH AF: 0.0463

GnomAD3 exomes AF: 0.0449 AC: 11087 AN: 246974 Hom.: 383 AF XY: 0.0455 AC XY: 6102 AN XY: 134182

Gnomad AFR exome AF: 0.00946

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0941

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0504

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0553

GnomAD4 exome AF: 0.0569 AC: 83126 AN: 1461382 Hom.: 2699 Cov.: 32 AF XY: 0.0559 AC XY: 40660 AN XY: 726966

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0299

Gnomad4 ASJ exome AF: 0.0901

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.0644

Gnomad4 OTH exome AF: 0.0552

GnomAD4 genome AF: 0.0440 AC: 6698 AN: 152322 Hom.: 192 Cov.: 33 AF XY: 0.0432 AC XY: 3219 AN XY: 74468

Gnomad4 AFR AF: 0.0110

Gnomad4 AMR AF: 0.0479

Gnomad4 ASJ AF: 0.0953

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.0494

Gnomad4 NFE AF: 0.0650

Gnomad4 OTH AF: 0.0458

Alfa AF: 0.0604 Hom.: 183

Bravo AF: 0.0430

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0662

EpiControl AF: 0.0651

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2013	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

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

Jul 17, 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	-0.64
Cadd	Benign	0.61
Dann	Benign	0.92

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: rs72552065; hg19: chr12-2788810; COSMIC: COSV59719622; COSMIC: COSV59719622;