rs113595214

chr12-2679449-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):c.5097C>T(p.Ala1699=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,556,730 control chromosomes in the GnomAD database, including 65 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (60 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.137

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 12-2679449-C-T is Benign according to our data. Variant chr12-2679449-C-T is described in ClinVar as [Benign]. Clinvar id is 93409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2679449-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00688 (1045/151934) while in subpopulation NFE AF= 0.0108 (731/67942). AF 95% confidence interval is 0.0101. There are 5 homozygotes in gnomad4. There are 480 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1044 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.5097C>T	p.Ala1699=	synonymous_variant	42/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.5097C>T	p.Ala1699=	synonymous_variant	42/47	ENST00000399603.6
CACNA1C-AS1	NR_045725.1	n.334-1552G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5097C>T	p.Ala1699=	synonymous_variant	42/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.5097C>T	p.Ala1699=	synonymous_variant	42/47	1	NM_000719.7
CACNA1C-AS1	ENST00000501371.5	n.295-1552G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00688 AC: 1044 AN: 151812 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0115

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00699 AC: 1293 AN: 184942 Hom.: 13 AF XY: 0.00684 AC XY: 674 AN XY: 98528

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.00562

Gnomad ASJ exome AF: 0.00426

Gnomad EAS exome AF: 0.0000665

Gnomad SAS exome AF: 0.00125

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.00947

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.00810 AC: 11383 AN: 1404796 Hom.: 60 Cov.: 31 AF XY: 0.00801 AC XY: 5542 AN XY: 692098

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.00580

Gnomad4 ASJ exome AF: 0.00303

Gnomad4 EAS exome AF: 0.0000526

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.0147

Gnomad4 NFE exome AF: 0.00884

Gnomad4 OTH exome AF: 0.00836

GnomAD4 genome AF: 0.00688 AC: 1045 AN: 151934 Hom.: 5 Cov.: 33 AF XY: 0.00646 AC XY: 480 AN XY: 74256

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.00518

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.0115

Gnomad4 NFE AF: 0.0108

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00952 Hom.: 3

Bravo AF: 0.00588

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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 17, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CACNA1C: BP4, BP7, BS1, BS2 -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 26, 2021

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2016

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	-0.31
Cadd	Benign	11
Dann	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113595214; hg19: chr12-2788615; COSMIC: COSV59760942; COSMIC: COSV59760942;