rs55792866

Variant names:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.372-15G>A variant causes a intron change. The variant allele was found at a frequency of 0.0251 in 1,264,380 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 88 hom., cov: 33)

Exomes 𝑓: 0.025 ( 451 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.47

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 12-2120310-G-A is Benign according to our data. Variant chr12-2120310-G-A is described in ClinVar as [Benign]. Clinvar id is 35768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2120310-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0294 (4469/152234) while in subpopulation AFR AF= 0.0487 (2024/41538). AF 95% confidence interval is 0.047. There are 88 homozygotes in gnomad4. There are 2154 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 4469 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.372-15G>A		intron_variant	Intron 2 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.372-15G>A		intron_variant	Intron 2 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.372-15G>A	intron_variant	Intron 2 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.372-15G>A	intron_variant	Intron 2 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.462-15G>A	intron_variant	Intron 2 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.372-15G>A	intron_variant	Intron 2 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.372-15G>A	intron_variant	Intron 2 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.462-15G>A	intron_variant	Intron 2 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.372-15G>A	intron_variant	Intron 2 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.372-15G>A	intron_variant	Intron 2 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.372-15G>A	intron_variant	Intron 2 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.462-15G>A	intron_variant	Intron 2 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.462-15G>A	intron_variant	Intron 2 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.462-15G>A	intron_variant	Intron 2 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.462-15G>A	intron_variant	Intron 2 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.372-15G>A	intron_variant	Intron 2 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.372-15G>A	intron_variant	Intron 2 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.372-15G>A	intron_variant	Intron 2 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.372-15G>A	intron_variant	Intron 2 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.372-15G>A	intron_variant	Intron 2 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.372-15G>A	intron_variant	Intron 2 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.372-15G>A	intron_variant	Intron 2 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.372-15G>A	intron_variant	Intron 2 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.372-15G>A	intron_variant	Intron 2 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.372-15G>A	intron_variant	Intron 2 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.372-15G>A	intron_variant	Intron 2 of 45			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000682152.1 link	c.321-15G>A	intron_variant	Intron 1 of 5			ENSP00000506759.1	A0A804HHT8
CACNA1C	ENST00000480911.6 link	n.372-15G>A	intron_variant	Intron 2 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0293

AC:

4461

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0487

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0156

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0377

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0235

GnomAD3 exomes

AF:

0.0234

AC:

5833

AN:

248948

Hom.:

AF XY:

0.0245

AC XY:

3306

AN XY:

135010

show subpopulations

Gnomad AFR exome

AF:

0.0463

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.0000555

Gnomad SAS exome

AF:

0.0371

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0265

Gnomad OTH exome

AF:

0.0184

GnomAD4 exome

AF:

0.0245

AC:

27248

AN:

1112146

Hom.:

451

Cov.:

AF XY:

0.0254

AC XY:

14500

AN XY:

570822

show subpopulations

Gnomad4 AFR exome

AF:

0.0484

Gnomad4 AMR exome

AF:

0.0118

Gnomad4 ASJ exome

AF:

0.0227

Gnomad4 EAS exome

AF:

0.000184

Gnomad4 SAS exome

AF:

0.0393

Gnomad4 FIN exome

AF:

0.0115

Gnomad4 NFE exome

AF:

0.0250

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0294

AC:

4469

AN:

152234

Hom.:

Cov.:

AF XY:

0.0289

AC XY:

2154

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.0487

Gnomad4 AMR

AF:

0.0156

Gnomad4 ASJ

AF:

0.0179

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0375

Gnomad4 FIN

AF:

0.0135

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0255

Hom.:

Bravo

AF:

0.0294

Asia WGS

AF:

0.0170

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 11, 2019

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.372-15G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 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 0.023 in 248948 control chromosomes in the gnomAD database, including 99 homozygotes. The observed variant frequency is approximately 2343-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.372-15G>A in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Benign:1

Sep 01, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Benign:1

Feb 04, 2025

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

-0.45

CADD

Benign

DANN

Benign

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over