chr12-2669044-G-A

Variant names:

• chr12-2669044-G-A
• rs369267978
• NM_000719.7:c.4726+9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.4726+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000299 in 1,583,480 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.60

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-AS2 (HGNC:):

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 12-2669044-G-A is Benign according to our data. Variant chr12-2669044-G-A is described in ClinVar as [Benign]. Clinvar id is 308156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000306 (438/1431184) while in subpopulation NFE AF = 0.000328 (356/1084090). AF 95% confidence interval is 0.0003. There are 0 homozygotes in GnomAdExome4. There are 208 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4726+9G>A		intron_variant	Intron 38 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4726+9G>A		intron_variant	Intron 38 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4726+9G>A		intron_variant	Intron 38 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4726+9G>A		intron_variant	Intron 38 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4960+9G>A		intron_variant	Intron 40 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4726+9G>A		intron_variant	Intron 38 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4693+9G>A		intron_variant	Intron 37 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4891+9G>A		intron_variant	Intron 39 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4870+9G>A		intron_variant	Intron 40 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4792+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4726+9G>A		intron_variant	Intron 38 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4726+9G>A		intron_variant	Intron 38 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4816+9G>A		intron_variant	Intron 38 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4816+9G>A		intron_variant	Intron 38 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4816+9G>A		intron_variant	Intron 38 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4816+9G>A		intron_variant	Intron 38 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4810+9G>A		intron_variant	Intron 39 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4801+9G>A		intron_variant	Intron 39 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4786+9G>A		intron_variant	Intron 39 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4777+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4768+9G>A		intron_variant	Intron 38 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4693+9G>A		intron_variant	Intron 37 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4693+9G>A		intron_variant	Intron 37 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4687+9G>A		intron_variant	Intron 37 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4726+9G>A		intron_variant	Intron 38 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4726+9G>A		intron_variant	Intron 38 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4717+9G>A		intron_variant	Intron 38 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4693+9G>A		intron_variant	Intron 37 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000204 AC: 51 AN: 249784 AF XY: 0.000236

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000306 AC: 438 AN: 1431184 Hom.: 0 Cov.: 25 AF XY: 0.000291 AC XY: 208 AN XY: 713986

Gnomad4 AFR exome AF: 0.0000609 AC: 2 AN: 32814

Gnomad4 AMR exome AF: 0.000134 AC: 6 AN: 44692

Gnomad4 ASJ exome AF: 0.00181 AC: 47 AN: 25952

Gnomad4 EAS exome AF: 0.0000253 AC: 1 AN: 39556

Gnomad4 SAS exome AF: 0.0000467 AC: 4 AN: 85680

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53314

Gnomad4 NFE exome AF: 0.000328 AC: 356 AN: 1084090

Gnomad4 Remaining exome AF: 0.000354 AC: 21 AN: 59360

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74472

Gnomad4 AFR AF: 0.0000963 AC: 0.0000962696 AN: 0.0000962696

Gnomad4 AMR AF: 0.000261 AC: 0.000261301 AN: 0.000261301

Gnomad4 ASJ AF: 0.00144 AC: 0.00144092 AN: 0.00144092

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000941 AC: 0.0000941442 AN: 0.0000941442

Gnomad4 NFE AF: 0.000294 AC: 0.000293979 AN: 0.000293979

Gnomad4 OTH AF: 0.000473 AC: 0.00047259 AN: 0.00047259

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.000310

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Mar 25, 2021

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.4726+9G>A alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 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 0.0002 in 249784 control chromosomes. The observed variant frequency is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4726+9G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

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

- -

Mar 31, 2015

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

Jul 16, 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

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0040
DANN	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs369267978; hg19: chr12-2778210;