rs1006737

Variant names:

• chr12-2236129-G-A
• rs1006737
• NM_000719.7:c.477+115699G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000719.7(CACNA1C):​c.477+115699G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,038 control chromosomes in the GnomAD database, including 10,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain risk allele (no stars).

• Frequency: Genomes: 𝑓 0.35 (10258 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Uncertain risk allele no assertion criteria provided O:1
• Conservation: PhyloP100: 0.248

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.477+115699G>A		intron_variant	Intron 3 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.477+115699G>A		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+115699G>A		intron_variant	Intron 3 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.477+115699G>A		intron_variant	Intron 3 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.567+115699G>A		intron_variant	Intron 3 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.477+115699G>A		intron_variant	Intron 3 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.477+115699G>A		intron_variant	Intron 3 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.567+115699G>A		intron_variant	Intron 3 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.477+115699G>A		intron_variant	Intron 3 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.477+115699G>A		intron_variant	Intron 3 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.477+115699G>A		intron_variant	Intron 3 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.567+115699G>A		intron_variant	Intron 3 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.567+115699G>A		intron_variant	Intron 3 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.567+115699G>A		intron_variant	Intron 3 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.567+115699G>A		intron_variant	Intron 3 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.477+115699G>A		intron_variant	Intron 3 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.477+115699G>A		intron_variant	Intron 3 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.477+115699G>A		intron_variant	Intron 3 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.477+115699G>A		intron_variant	Intron 3 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.477+115699G>A		intron_variant	Intron 3 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.477+115699G>A		intron_variant	Intron 3 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.477+115699G>A		intron_variant	Intron 3 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.477+115699G>A		intron_variant	Intron 3 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.477+115699G>A		intron_variant	Intron 3 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.477+115699G>A		intron_variant	Intron 3 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.477+115699G>A		intron_variant	Intron 3 of 45			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.426+115699G>A		intron_variant	Intron 2 of 5			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.477+115699G>A		intron_variant	Intron 3 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53833 AN: 151920 Hom.: 10263 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.328

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

GnomAD4 genome AF: 0.354 AC: 53869 AN: 152038 Hom.: 10258 Cov.: 32 AF XY: 0.349 AC XY: 25918 AN XY: 74314

Gnomad4 AFR AF: 0.479 AC: 0.47877 AN: 0.47877

Gnomad4 AMR AF: 0.286 AC: 0.285696 AN: 0.285696

Gnomad4 ASJ AF: 0.296 AC: 0.296136 AN: 0.296136

Gnomad4 EAS AF: 0.0514 AC: 0.0513712 AN: 0.0513712

Gnomad4 SAS AF: 0.247 AC: 0.247406 AN: 0.247406

Gnomad4 FIN AF: 0.318 AC: 0.318466 AN: 0.318466

Gnomad4 NFE AF: 0.335 AC: 0.335035 AN: 0.335035

Gnomad4 OTH AF: 0.323 AC: 0.322749 AN: 0.322749

Alfa AF: 0.329 Hom.: 29398

Bravo AF: 0.353

Asia WGS AF: 0.150 AC: 527 AN: 3478

ClinVar

Significance: Uncertain risk allele

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Post-traumatic stress disorder Other:1

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Department of Behavioral Medicine, National Institute of Mental Health, National Center of Neurology and Psychiatry

Significance: Uncertain risk allele

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.63
Mutation Taster		=100/0	polymorphism (auto)

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: rs1006737; hg19: chr12-2345295;