rs201345843

Variant names:

• chr12-2651663-C-T
• rs201345843
• NM_000719.7:c.3969C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.3969C>T​(p.Ile1323Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.000195 in 1,613,842 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 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 4.93
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 12-2651663-C-T is Benign according to our data. Variant chr12-2651663-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93405.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4203C>T	p.Ile1401Ile	synonymous_variant	Exon 34 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3936C>T	p.Ile1312Ile	synonymous_variant	Exon 31 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4134C>T	p.Ile1378Ile	synonymous_variant	Exon 33 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4113C>T	p.Ile1371Ile	synonymous_variant	Exon 34 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4035C>T	p.Ile1345Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4059C>T	p.Ile1353Ile	synonymous_variant	Exon 32 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4059C>T	p.Ile1353Ile	synonymous_variant	Exon 32 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4059C>T	p.Ile1353Ile	synonymous_variant	Exon 32 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4059C>T	p.Ile1353Ile	synonymous_variant	Exon 32 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4053C>T	p.Ile1351Ile	synonymous_variant	Exon 33 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4044C>T	p.Ile1348Ile	synonymous_variant	Exon 33 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4029C>T	p.Ile1343Ile	synonymous_variant	Exon 33 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4020C>T	p.Ile1340Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4011C>T	p.Ile1337Ile	synonymous_variant	Exon 32 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3936C>T	p.Ile1312Ile	synonymous_variant	Exon 31 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3936C>T	p.Ile1312Ile	synonymous_variant	Exon 31 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3930C>T	p.Ile1310Ile	synonymous_variant	Exon 31 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3969C>T	p.Ile1323Ile	synonymous_variant	Exon 32 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3960C>T	p.Ile1320Ile	synonymous_variant	Exon 32 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3936C>T	p.Ile1312Ile	synonymous_variant	Exon 31 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000641 AC: 16 AN: 249526 AF XY: 0.0000591

Gnomad AFR exome AF: 0.00

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: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000208 AC: 304 AN: 1461664 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 156 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1111840

Other (OTH) AF: 0.0000663 AC: 4 AN: 60374

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.0000718

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Oct 16, 2013

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 16, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3969 C>T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3969 C>T variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.3969 C>T variant results in a synonymous amino acid substitution, I1323I, and in silico splice prediction programs are unable to predict whether this nucleotide substitution has an impact on normal gene splicing. Additionally, the majority of variants in the CACNA1C gene are missense changes (Stenson et al., 2014), indicating haploinsufficiency of CACNA1C may not be sufficient to cause disease. Nevertheless, this substitution occurs at a position that is conserved across species. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. -

not specified Benign:1

Nov 06, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CACNA1C c.3969C>T (p.Ile1323Ile) variant involves the alteration of a conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 15/277196 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000118 (15/126706). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant has been reported in the literature, without strong evidence for causality. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as benign. -

CACNA1C-related disorder Benign:1

Oct 14, 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

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Feb 25, 2021

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	-0.19
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		4.9

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: rs201345843; hg19: chr12-2760829;