rs374857905

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6BP7BS2

The NM_000719.7(CACNA1C):c.2391G>A(p.Gly797Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,608,514 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 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.75

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 -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 12-2585427-G-A is Benign according to our data. Variant chr12-2585427-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286500.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}.

BP7

Synonymous conserved (PhyloP=1.75 with no splicing effect.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.2481G>A	p.Gly827Gly	synonymous_variant	Exon 17 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.2556G>A	p.Gly852Gly	synonymous_variant	Exon 18 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.2481G>A	p.Gly827Gly	synonymous_variant	Exon 17 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.2481G>A	p.Gly827Gly	synonymous_variant	Exon 17 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.2481G>A	p.Gly827Gly	synonymous_variant	Exon 17 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.2481G>A	p.Gly827Gly	synonymous_variant	Exon 17 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.2466G>A	p.Gly822Gly	synonymous_variant	Exon 18 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.2466G>A	p.Gly822Gly	synonymous_variant	Exon 18 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.2382G>A	p.Gly794Gly	synonymous_variant	Exon 17 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.2391G>A	p.Gly797Gly	synonymous_variant	Exon 17 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*998G>A		non_coding_transcript_exon_variant	Exon 15 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.*998G>A		3_prime_UTR_variant	Exon 15 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000185

AC:

AN:

238458

Hom.:

AF XY:

0.000216

AC XY:

AN XY:

129388

show subpopulations

Gnomad AFR exome

AF:

0.0000673

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000479

Gnomad NFE exome

AF:

0.000382

Gnomad OTH exome

AF:

0.000171

GnomAD4 exome

AF:

0.000193

AC:

281

AN:

1456320

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

150

AN XY:

723918

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.0000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000755

Gnomad4 NFE exome

AF:

0.000232

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000184

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000223

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1C-related disorder

Benign:1

Feb 23, 2024

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 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 26, 2018

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

-0.44

CADD

Benign

3.5

DANN

Benign

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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