chr12-2611965-C-A

Variant names:

• chr12-2611965-C-A
• rs201258230
• NM_000719.7:c.3780C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.3780C>A​(p.Gly1260Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00161 in 1,613,512 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0016 (10 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.130
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 12-2611965-C-A is Benign according to our data. Variant chr12-2611965-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93403.
• BP7: Synonymous conserved (PhyloP=0.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00132 (201/152250) while in subpopulation AMR AF = 0.00333 (51/15296). AF 95% confidence interval is 0.00261. There are 0 homozygotes in GnomAd4. There are 92 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 201 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3930C>A	p.Gly1310Gly	synonymous_variant	Exon 30 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3945C>A	p.Gly1315Gly	synonymous_variant	Exon 30 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3840C>A	p.Gly1280Gly	synonymous_variant	Exon 30 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	Exon 29 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	Exon 29 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	Exon 29 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3870C>A	p.Gly1290Gly	synonymous_variant	Exon 29 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3855C>A	p.Gly1285Gly	synonymous_variant	Exon 30 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3840C>A	p.Gly1280Gly	synonymous_variant	Exon 30 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3855C>A	p.Gly1285Gly	synonymous_variant	Exon 30 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3771C>A	p.Gly1257Gly	synonymous_variant	Exon 29 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3780C>A	p.Gly1260Gly	synonymous_variant	Exon 29 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2387C>A		non_coding_transcript_exon_variant	Exon 27 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2387C>A		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 201 AN: 152132 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00213 AC: 534 AN: 250230 AF XY: 0.00234

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00258

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.0000550

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00164 AC: 2397 AN: 1461262 Hom.: 10 Cov.: 29 AF XY: 0.00170 AC XY: 1237 AN XY: 727012

African (AFR) AF: 0.000179 AC: 6 AN: 33464

American (AMR) AF: 0.00293 AC: 131 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00446 AC: 385 AN: 86234

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53412

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5764

European-Non Finnish (NFE) AF: 0.00147 AC: 1633 AN: 1111466

Other (OTH) AF: 0.00245 AC: 148 AN: 60378

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152250 Hom.: 0 Cov.: 31 AF XY: 0.00124 AC XY: 92 AN XY: 74446

African (AFR) AF: 0.000193 AC: 8 AN: 41548

American (AMR) AF: 0.00333 AC: 51 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00144 AC: 98 AN: 68010

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00193

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 31, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4, BS1 -

not specified Benign:3

Apr 10, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CACNA1C-related disorder Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Nov 19, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	8.8
DANN	Benign	0.74
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs201258230; hg19: chr12-2721131;