ENST00000344100.7:c.4000G>A

Variant names:

• chr12-2651628-G-A
• rs41276706
• ENST00000344100.7:c.4000G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000344100.7(CACNA1C):​c.4000G>A​(p.Asp1334Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000305 in 1,613,770 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1334E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: CACNA1C ENST00000344100.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.200
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.041235715).
• BP6: Variant 12-2651628-G-A is Benign according to our data. Variant chr12-2651628-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190617.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000315 (461/1461672) while in subpopulation SAS AF = 0.000765 (66/86256). AF 95% confidence interval is 0.000616. There are 2 homozygotes in GnomAdExome4. There are 237 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3946-12G>A		intron_variant	Intron 31 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3946-12G>A		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.4000G>A	p.Asp1334Asn	missense_variant	Exon 32 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000399603.6	c.3946-12G>A		intron_variant	Intron 31 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3946-12G>A		intron_variant	Intron 31 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4180-12G>A		intron_variant	Intron 33 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3946-12G>A		intron_variant	Intron 31 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3913-12G>A		intron_variant	Intron 30 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4111-12G>A		intron_variant	Intron 32 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4090-12G>A		intron_variant	Intron 33 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000327702.12	c.3946-12G>A		intron_variant	Intron 31 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3946-12G>A		intron_variant	Intron 31 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4036-12G>A		intron_variant	Intron 31 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4036-12G>A		intron_variant	Intron 31 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4036-12G>A		intron_variant	Intron 31 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4036-12G>A		intron_variant	Intron 31 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4030-12G>A		intron_variant	Intron 32 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4021-12G>A		intron_variant	Intron 32 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4006-12G>A		intron_variant	Intron 32 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3997-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3988-12G>A		intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3913-12G>A		intron_variant	Intron 30 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3913-12G>A		intron_variant	Intron 30 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3907-12G>A		intron_variant	Intron 30 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3946-12G>A		intron_variant	Intron 31 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3946-12G>A		intron_variant	Intron 31 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3937-12G>A		intron_variant	Intron 31 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3913-12G>A		intron_variant	Intron 30 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000233 AC: 58 AN: 249296 AF XY: 0.000311

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000315 AC: 461 AN: 1461672 Hom.: 2 Cov.: 33 AF XY: 0.000326 AC XY: 237 AN XY: 727126

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000650 AC: 17 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000765 AC: 66 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000317 AC: 353 AN: 1111856

Other (OTH) AF: 0.000265 AC: 16 AN: 60374

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152098 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74282

African (AFR) AF: 0.000169 AC: 7 AN: 41422

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: PP2, PP3 -

Mar 18, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26220970) -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:2

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CACNA1C c.3946-12G>A alters a conserved nucleotide located at a position not widely known to affect splicing. Two of two in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 249296 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 49 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05). c.3946-12G>A has been reported in the literature in at-least one individual with Brugada syndrome, without strong evidence of causality (example: Di Resta_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Timothy Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 190617). Based on the evidence outlined above, the variant was classified as benign. -

CACNA1C-related disorder Benign:1

Aug 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Benign:1

Apr 17, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.3
DANN	Uncertain	0.97
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.041	T
MetaSVM	Benign	-0.28	T
PhyloP100		-0.20
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.27
Sift	Benign	0.16	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.063
MVP		0.59
ClinPred		0.014	T
GERP RS		-0.44
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs41276706; hg19: chr12-2760794;