rs112539787

Variant names:

• chr12-2493239-C-T
• rs112539787
• NM_000719.7:c.966C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000719.7(CACNA1C):​c.966C>T​(p.His322His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,614,042 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.960

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-2493239-C-T is Benign according to our data. Variant chr12-2493239-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2493239-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.96 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000525 (80/152356) while in subpopulation EAS AF= 0.00986 (51/5172). AF 95% confidence interval is 0.0077. There are 3 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.966C>T	p.His322His	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.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1056C>T	p.His352His	synonymous_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.957C>T	p.His319His	synonymous_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.966C>T	p.His322His	synonymous_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.903C>T	p.His301His	synonymous_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.966C>T		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 78 AN: 152238 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00984

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000735 AC: 183 AN: 249096 Hom.: 0 AF XY: 0.000540 AC XY: 73 AN XY: 135126

Gnomad AFR exome AF: 0.000193

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00963

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000244 AC: 356 AN: 1461686 Hom.: 4 Cov.: 31 AF XY: 0.000205 AC XY: 149 AN XY: 727124

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00627

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000525 AC: 80 AN: 152356 Hom.: 3 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74506

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00986

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000525

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Apr 17, 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.966C>T (p.His322His) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 85/121084 control chromosomes (1 homozygote) at a frequency of 0.000702, which is approximately 70 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this variant is likely a benign polymorphism. This variant has been reported in a cohort of Long QT patients with comparable MAF in controls. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 07, 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. -

CACNA1C-related disorder Benign:1

Nov 08, 2023

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 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 03, 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	-0.82
CADD	Benign	2.1
DANN	Benign	0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs112539787; hg19: chr12-2602405;