NM_000719.7:c.1176G>T

Variant names:

• chr12-2504904-G-T
• rs1051360
• NM_000719.7:c.1176G>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.1176G>T​(p.Gly392Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,606,526 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.49
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-2504904-G-T is Benign according to our data. Variant chr12-2504904-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 166767.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.002 (303/151736) while in subpopulation NFE AF = 0.00352 (239/67866). AF 95% confidence interval is 0.00315. There are 1 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 303 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1217+365G>T		intron_variant	Intron 8 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399655.6	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1266G>T	p.Gly422Gly	synonymous_variant	Exon 8 of 50			ENSP00000507184.1
CACNA1C	ENST00000347598.9	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399638.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000683482.1	c.1167G>T	p.Gly389Gly	synonymous_variant	Exon 8 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1176G>T	p.Gly392Gly	synonymous_variant	Exon 8 of 46			ENSP00000507309.1
CACNA1C	ENST00000399603.6	c.1217+365G>T		intron_variant	Intron 8 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.1217+365G>T		intron_variant	Intron 8 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1217+365G>T		intron_variant	Intron 8 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1307+365G>T		intron_variant	Intron 8 of 47			ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.1217+365G>T		intron_variant	Intron 8 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1307+365G>T		intron_variant	Intron 8 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1307+365G>T		intron_variant	Intron 8 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1307+365G>T		intron_variant	Intron 8 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1307+365G>T		intron_variant	Intron 8 of 46			ENSP00000506882.1
CACNA1C	ENST00000399641.6	c.1217+365G>T		intron_variant	Intron 8 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000682835.1	c.1217+365G>T		intron_variant	Intron 8 of 46			ENSP00000507282.1
CACNA1C	ENST00000480911.6	n.1113+11518G>T		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 303 AN: 151618 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00352

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00197 AC: 490 AN: 248890 AF XY: 0.00205

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00288 AC: 4197 AN: 1454790 Hom.: 9 Cov.: 28 AF XY: 0.00284 AC XY: 2060 AN XY: 724284

African (AFR) AF: 0.000330 AC: 11 AN: 33340

American (AMR) AF: 0.00163 AC: 73 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000537 AC: 14 AN: 26080

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86034

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53392

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00352 AC: 3892 AN: 1105718

Other (OTH) AF: 0.00171 AC: 103 AN: 60122

GnomAD4 genome AF: 0.00200 AC: 303 AN: 151736 Hom.: 1 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74178

African (AFR) AF: 0.000653 AC: 27 AN: 41354

American (AMR) AF: 0.000983 AC: 15 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00352 AC: 239 AN: 67866

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00285

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 13, 2019

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.1176G>T alters a conserved nucleotide resulting in a synonymous change. 5/5 computational 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 0.002 in 248890 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 196 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. The variant, c.1176G>T, has been reported in the literature in individuals affected with long-QT syndrome (Ghouse_2015, Wemhoner_2015). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign (n=2), likely benign (n=2)). Based on the evidence outlined above, the variant was classified as benign. -

Jan 02, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

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 -

May 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1C-related disorder Benign:1

May 01, 2019

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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jan 22, 2016

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	-0.46
CADD	Benign	9.5
DANN	Benign	0.71
PhyloP100		1.5
PromoterAI		-0.0016	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1051360; hg19: chr12-2614070; COSMIC: COSV59762972;