rs1544514

chr12-2449020-G-Achr12-2449020-G-Cchr12-2449020-G-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.522G>A(p.Ala174=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,603,596 control chromosomes in the GnomAD database, including 31,499 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2420 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29079 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0370

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2449020-G-A is Benign according to our data. Variant chr12-2449020-G-A is described in ClinVar as [Benign]. Clinvar id is 93412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449020-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.037 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.522G>A	p.Ala174=	synonymous_variant	4/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.522G>A	p.Ala174=	synonymous_variant	4/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.522G>A	p.Ala174=	synonymous_variant	4/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.522G>A	p.Ala174=	synonymous_variant	4/47	1	NM_000719.7
	ENST00000649808.1	n.208+133C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25617 AN: 151994 Hom.: 2420 Cov.: 33

Gnomad AFR AF: 0.0971

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.291

Gnomad EAS AF: 0.0615

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.176 AC: 42748 AN: 242448 Hom.: 4157 AF XY: 0.179 AC XY: 23507 AN XY: 131480

Gnomad AFR exome AF: 0.0951

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.0644

Gnomad SAS exome AF: 0.148

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.196 AC: 284454 AN: 1451484 Hom.: 29079 Cov.: 28 AF XY: 0.196 AC XY: 141705 AN XY: 722124

Gnomad4 AFR exome AF: 0.0942

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.0719

Gnomad4 SAS exome AF: 0.150

Gnomad4 FIN exome AF: 0.166

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.168 AC: 25623 AN: 152112 Hom.: 2420 Cov.: 33 AF XY: 0.166 AC XY: 12325 AN XY: 74372

Gnomad4 AFR AF: 0.0970

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.291

Gnomad4 EAS AF: 0.0617

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.168

Alfa AF: 0.203 Hom.: 5821

Bravo AF: 0.167

Asia WGS AF: 0.0870 AC: 305 AN: 3478

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	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2013	- -

Timothy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Mar 09, 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	-0.39
Cadd	Benign	13
Dann	Benign	0.78

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: rs1544514; hg19: chr12-2558186; COSMIC: COSV59719439;