12-2274839-T-G

Variant names:

• chr12-2274839-T-G
• rs2238057
• NM_000719.7:c.477+154409T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000719.7(CACNA1C):​c.477+154409T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 152,026 control chromosomes in the GnomAD database, including 21,070 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.50 (21070 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.430

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-IT3 (HGNC:41314): (CACNA1C intronic transcript 3)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-2274839-T-G is Benign according to our data. Variant chr12-2274839-T-G is described in ClinVar as [Benign]. Clinvar id is 1573869.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.477+154409T>G		intron_variant	Intron 3 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.477+154409T>G		intron_variant	Intron 3 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.477+154409T>G		intron_variant	Intron 3 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.477+154409T>G		intron_variant	Intron 3 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.567+154409T>G		intron_variant	Intron 3 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.477+154409T>G		intron_variant	Intron 3 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.477+154409T>G		intron_variant	Intron 3 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.567+154409T>G		intron_variant	Intron 3 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.477+154409T>G		intron_variant	Intron 3 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.477+154409T>G		intron_variant	Intron 3 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.477+154409T>G		intron_variant	Intron 3 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.567+154409T>G		intron_variant	Intron 3 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.567+154409T>G		intron_variant	Intron 3 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.567+154409T>G		intron_variant	Intron 3 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.567+154409T>G		intron_variant	Intron 3 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.477+154409T>G		intron_variant	Intron 3 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.477+154409T>G		intron_variant	Intron 3 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.477+154409T>G		intron_variant	Intron 3 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.477+154409T>G		intron_variant	Intron 3 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.477+154409T>G		intron_variant	Intron 3 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.477+154409T>G		intron_variant	Intron 3 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.477+154409T>G		intron_variant	Intron 3 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.477+154409T>G		intron_variant	Intron 3 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.477+154409T>G		intron_variant	Intron 3 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.477+154409T>G		intron_variant	Intron 3 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.477+154409T>G		intron_variant	Intron 3 of 45			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.426+154409T>G		intron_variant	Intron 2 of 5			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.477+154409T>G		intron_variant	Intron 3 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75947 AN: 151908 Hom.: 21027 Cov.: 32

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.450

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.333

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.500 AC: 76041 AN: 152026 Hom.: 21070 Cov.: 32 AF XY: 0.494 AC XY: 36674 AN XY: 74290

Gnomad4 AFR AF: 0.749

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.421

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.450

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.456

Alfa AF: 0.420 Hom.: 22662

Bravo AF: 0.509

Asia WGS AF: 0.400 AC: 1391 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	7.0
DANN	Benign	0.72

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: rs2238057; hg19: chr12-2384005; COSMIC: COSV59749674;