12-2053203-G-A

Variant names:

• chr12-2053203-G-A
• rs11062091
• NM_000719.7:c.-360G>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.-360G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,000,742 control chromosomes in the GnomAD database, including 14,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2316 hom., cov: 31)
  • Exomes 𝑓: 0.17 (12568 hom.)
• Consequence: CACNA1C NM_000719.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.577

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-2053203-G-A is Benign according to our data. Variant chr12-2053203-G-A is described in ClinVar as [Benign]. Clinvar id is 683258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454	c.-360G>A		5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000347598	c.-360G>A		5_prime_UTR_variant	Exon 1 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000327702	c.-360G>A		5_prime_UTR_variant	Exon 1 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000335762	c.-360G>A		5_prime_UTR_variant	Exon 1 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399641	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000682835	c.-360G>A		5_prime_UTR_variant	Exon 1 of 47			ENSP00000507282.1
CACNA1C	ENST00000682544.1	c.140-62021G>A		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-62021G>A		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-62021G>A		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-62021G>A		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-62021G>A		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-62021G>A		intron_variant	Intron 1 of 46			ENSP00000506882.1
CACNA1C	ENST00000399617.6	c.-360G>A		upstream_gene_variant		5		ENSP00000382526.1
CACNA1C	ENST00000683482.1	c.-360G>A		upstream_gene_variant				ENSP00000507169.1

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26000 AN: 151546 Hom.: 2316 Cov.: 31

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.172 AC: 146077 AN: 849084 Hom.: 12568 Cov.: 31 AF XY: 0.172 AC XY: 67534 AN XY: 393368

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.131

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.172 AC: 26018 AN: 151658 Hom.: 2316 Cov.: 31 AF XY: 0.172 AC XY: 12766 AN XY: 74110

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.127

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.156

Alfa AF: 0.0895 Hom.: 137

Bravo AF: 0.165

Asia WGS AF: 0.182 AC: 630 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	11
DANN	Benign	0.95

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11062091; hg19: chr12-2162369;