rs2302729

Positions:

• chr12-2674806-T-C

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.4828+164T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 152,134 control chromosomes in the GnomAD database, including 40,573 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.71 (40573 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.05

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 12-2674806-T-C is Benign according to our data. Variant chr12-2674806-T-C is described in ClinVar as [Benign]. Clinvar id is 671811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4828+164T>C		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4828+164T>C		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4828+164T>C		intron_variant		5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.4828+164T>C		intron_variant		1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108052 AN: 152016 Hom.: 40563 Cov.: 33

Gnomad AFR AF: 0.450

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.840

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.734

Gnomad NFE AF: 0.829

Gnomad OTH AF: 0.726

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.711 AC: 108094 AN: 152134 Hom.: 40573 Cov.: 33 AF XY: 0.714 AC XY: 53110 AN XY: 74386

Gnomad4 AFR AF: 0.450

Gnomad4 AMR AF: 0.741

Gnomad4 ASJ AF: 0.840

Gnomad4 EAS AF: 0.624

Gnomad4 SAS AF: 0.848

Gnomad4 FIN AF: 0.859

Gnomad4 NFE AF: 0.829

Gnomad4 OTH AF: 0.727

Alfa AF: 0.814 Hom.: 97959

Bravo AF: 0.689

Asia WGS AF: 0.724 AC: 2514 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.17
DANN	Benign	0.73

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: rs2302729; hg19: chr12-2783972;