12-2651630-C-T

Variant names:

• chr12-2651630-C-T
• rs370630496
• ENST00000344100.7:c.4002C>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001129829.2(CACNA1C):​c.4002C>T​(p.Asp1334Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: CACNA1C NM_001129829.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.180

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 12-2651630-C-T is Benign according to our data. Variant chr12-2651630-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 308149.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-2651630-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.18 with no splicing effect.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3946-10C>T		intron_variant	Intron 31 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3946-10C>T		intron_variant	Intron 31 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000344100.7	c.4002C>T	p.Asp1334Asp	synonymous_variant	Exon 32 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000399603.6	c.3946-10C>T		intron_variant	Intron 31 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3946-10C>T		intron_variant	Intron 31 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4180-10C>T		intron_variant	Intron 33 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3946-10C>T		intron_variant	Intron 31 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3913-10C>T		intron_variant	Intron 30 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4111-10C>T		intron_variant	Intron 32 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4090-10C>T		intron_variant	Intron 33 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000327702.12	c.3946-10C>T		intron_variant	Intron 31 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3946-10C>T		intron_variant	Intron 31 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4036-10C>T		intron_variant	Intron 31 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4036-10C>T		intron_variant	Intron 31 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4036-10C>T		intron_variant	Intron 31 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4036-10C>T		intron_variant	Intron 31 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4030-10C>T		intron_variant	Intron 32 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4021-10C>T		intron_variant	Intron 32 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4006-10C>T		intron_variant	Intron 32 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3997-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3988-10C>T		intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3913-10C>T		intron_variant	Intron 30 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3913-10C>T		intron_variant	Intron 30 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3907-10C>T		intron_variant	Intron 30 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3946-10C>T		intron_variant	Intron 31 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3946-10C>T		intron_variant	Intron 31 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3937-10C>T		intron_variant	Intron 31 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3913-10C>T		intron_variant	Intron 30 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000481 AC: 12 AN: 249314 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135248

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461666 Hom.: 0 Cov.: 33 AF XY: 0.0000413 AC XY: 30 AN XY: 727130

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74330

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Benign:1

Dec 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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	-0.39
CADD	Benign	16
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: rs370630496; hg19: chr12-2760796; COSMIC: COSV59702683;