rs371931644

Positions:

chr12-2679629-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.5277G>A(p.Ser1759Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,862 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.40

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:

CACNA1C-AS1 (HGNC:):

CACNA1C-AS1 links:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 12-2679629-G-A is Benign according to our data. Variant chr12-2679629-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 416877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2679629-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.4 with no splicing effect.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5511G>A	p.Ser1837Ser	synonymous_variant	44/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5244G>A	p.Ser1748Ser	synonymous_variant	41/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.5442G>A	p.Ser1814Ser	synonymous_variant	43/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5421G>A	p.Ser1807Ser	synonymous_variant	44/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5400G>A	p.Ser1800Ser	synonymous_variant	42/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5367G>A	p.Ser1789Ser	synonymous_variant	42/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5367G>A	p.Ser1789Ser	synonymous_variant	42/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5367G>A	p.Ser1789Ser	synonymous_variant	42/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5367G>A	p.Ser1789Ser	synonymous_variant	42/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5361G>A	p.Ser1787Ser	synonymous_variant	43/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5352G>A	p.Ser1784Ser	synonymous_variant	43/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5337G>A	p.Ser1779Ser	synonymous_variant	43/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5334G>A	p.Ser1778Ser	synonymous_variant	42/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5334G>A	p.Ser1778Ser	synonymous_variant	42/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5334G>A	p.Ser1778Ser	synonymous_variant	42/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5328G>A	p.Ser1776Ser	synonymous_variant	42/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5319G>A	p.Ser1773Ser	synonymous_variant	42/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5301G>A	p.Ser1767Ser	synonymous_variant	41/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5301G>A	p.Ser1767Ser	synonymous_variant	41/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5295G>A	p.Ser1765Ser	synonymous_variant	41/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5277G>A	p.Ser1759Ser	synonymous_variant	42/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5268G>A	p.Ser1756Ser	synonymous_variant	42/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5244G>A	p.Ser1748Ser	synonymous_variant	41/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000283

AC:

AN:

247394

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134398

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461576

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152286

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000529

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1C-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2024

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). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

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

-0.57

CADD

Benign

2.1

DANN

Benign

0.88

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