rs369079645

Variant names:

• chr12-2493200-A-G
• rs369079645
• NM_000719.7:c.927A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000719.7(CACNA1C):​c.927A>G​(p.Ala309Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 1.14
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 12-2493200-A-G is Benign according to our data. Variant chr12-2493200-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416869.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1017A>G	p.Ala339Ala	synonymous_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1017A>G	p.Ala339Ala	synonymous_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1017A>G	p.Ala339Ala	synonymous_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1017A>G	p.Ala339Ala	synonymous_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1017A>G	p.Ala339Ala	synonymous_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1017A>G	p.Ala339Ala	synonymous_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.918A>G	p.Ala306Ala	splice_region_variant, synonymous_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.927A>G	p.Ala309Ala	synonymous_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.927A>G		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000682152.1	c.866-2A>G		splice_acceptor_variant, intron_variant	Intron 5 of 5			ENSP00000506759.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 247824 AF XY: 0.0000149

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726872

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44698

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111588

Other (OTH) AF: 0.0000166 AC: 1 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74356

African (AFR) AF: 0.000241 AC: 10 AN: 41452

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jun 27, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Oct 03, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Sep 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 07, 2019

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	-0.48
CADD	Benign	13
DANN	Benign	0.72
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369079645; hg19: chr12-2602366;