rs1544515

Positions:

• chr12-2449132-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.617+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,503,642 control chromosomes in the GnomAD database, including 48,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5594 hom., cov: 32)
  • Exomes 𝑓: 0.25 (43383 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.741

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-2449132-G-A is Benign according to our data. Variant chr12-2449132-G-A is described in ClinVar as [Benign]. Clinvar id is 93420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2449132-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.617+17G>A		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.617+17G>A		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.617+17G>A		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.617+17G>A		intron_variant		1	NM_000719.7
	ENST00000649808.1	n.208+21C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.269 AC: 40815 AN: 151714 Hom.: 5583 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.228

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.249

GnomAD3 exomes AF: 0.251 AC: 34268 AN: 136684 Hom.: 4403 AF XY: 0.254 AC XY: 18151 AN XY: 71382

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.179

Gnomad SAS exome AF: 0.302

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.250 AC: 338422 AN: 1351810 Hom.: 43383 Cov.: 28 AF XY: 0.252 AC XY: 167424 AN XY: 663532

Gnomad4 AFR exome AF: 0.329

Gnomad4 AMR exome AF: 0.187

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.252

GnomAD4 genome AF: 0.269 AC: 40875 AN: 151832 Hom.: 5594 Cov.: 32 AF XY: 0.269 AC XY: 19936 AN XY: 74190

Gnomad4 AFR AF: 0.322

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.247

Gnomad4 NFE AF: 0.251

Gnomad4 OTH AF: 0.254

Alfa AF: 0.263 Hom.: 2253

Bravo AF: 0.270

Asia WGS AF: 0.300 AC: 1041 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	Eurofins Ntd Llc (ga)	Jul 23, 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. -

Timothy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.51

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: rs1544515; hg19: chr12-2558298; COSMIC: COSV59695531;