rs116491041

Variant names:

• chr12-2567693-C-T
• rs116491041
• NM_000719.7:c.1794C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.1794C>T​(p.Gly598Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000335 in 1,613,462 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G598G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.312
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 12-2567693-C-T is Benign according to our data. Variant chr12-2567693-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136615.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.312 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00181 (276/152258) while in subpopulation AFR AF = 0.00626 (260/41548). AF 95% confidence interval is 0.00563. There are 2 homozygotes in GnomAd4. There are 141 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1884C>T	p.Gly628Gly	synonymous_variant	Exon 13 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1959C>T	p.Gly653Gly	synonymous_variant	Exon 14 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1884C>T	p.Gly628Gly	synonymous_variant	Exon 13 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1884C>T	p.Gly628Gly	synonymous_variant	Exon 13 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1884C>T	p.Gly628Gly	synonymous_variant	Exon 13 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1884C>T	p.Gly628Gly	synonymous_variant	Exon 13 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1869C>T	p.Gly623Gly	synonymous_variant	Exon 14 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1869C>T	p.Gly623Gly	synonymous_variant	Exon 14 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1785C>T	p.Gly595Gly	synonymous_variant	Exon 13 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1794C>T	p.Gly598Gly	synonymous_variant	Exon 13 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*401C>T		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*401C>T		3_prime_UTR_variant	Exon 11 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152140 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000510 AC: 127 AN: 248970 AF XY: 0.000474

Gnomad AFR exome AF: 0.00685

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000181 AC: 265 AN: 1461204 Hom.: 1 Cov.: 31 AF XY: 0.000151 AC XY: 110 AN XY: 726876

African (AFR) AF: 0.00642 AC: 215 AN: 33468

American (AMR) AF: 0.000358 AC: 16 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111570

Other (OTH) AF: 0.000464 AC: 28 AN: 60364

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152258 Hom.: 2 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74434

African (AFR) AF: 0.00626 AC: 260 AN: 41548

American (AMR) AF: 0.000654 AC: 10 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000898 Hom.: 0

Bravo AF: 0.00195

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 17, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

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:2

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4, BP7, BS1 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Long QT syndrome Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 21, 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	-0.47
CADD	Benign	5.0
DANN	Benign	0.78
PhyloP100		-0.31

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: rs116491041; hg19: chr12-2676859;