rs763738559

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP2BS2

The NM_000719.7(CACNA1C):c.1753G>A(p.Val585Met) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000061 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 5.88

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000719.7

PP2

Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 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.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1843G>A	p.Val615Met	missense_variant	Exon 13 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1918G>A	p.Val640Met	missense_variant	Exon 14 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1843G>A	p.Val615Met	missense_variant	Exon 13 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1843G>A	p.Val615Met	missense_variant	Exon 13 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1843G>A	p.Val615Met	missense_variant	Exon 13 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1843G>A	p.Val615Met	missense_variant	Exon 13 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1828G>A	p.Val610Met	missense_variant	Exon 14 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1828G>A	p.Val610Met	missense_variant	Exon 14 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.1744G>A	p.Val582Met	missense_variant	Exon 13 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1753G>A	p.Val585Met	missense_variant	Exon 13 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*360G>A		non_coding_transcript_exon_variant	Exon 11 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.*360G>A		3_prime_UTR_variant	Exon 11 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152148

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000323

AC:

AN:

247354

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

134076

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000626

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000609

AC:

AN:

1460892

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726608

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152148

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74324

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Clinical Genetics, Academic Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 30, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has been reported in an individual with sudden unexplained death at 36 years of age, and cardiac findings on autopsy showed interstitial fibrosis and myocyte hypertrophy (Shanks et al., 2018); however, a frameshift variant in the A-band of the TTN gene was also identified and no family history or segregation details were reported.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29915097) -

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

Uncertain:1

Aug 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome

Uncertain:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 585 of the CACNA1C protein (p.Val585Met). This variant is present in population databases (rs763738559, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 519274). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Apr 07, 2022

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_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.52

MetaRNN

Uncertain

0.44

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.95

MutationAssessor

Benign

-0.17

.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.6

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.63

Sift

Benign

0.23

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 1.0, 0.95, 0.86, 0.98

.;D;D;P;D;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D

Vest4

0.44

MVP

0.77

MPC

1.8

ClinPred

0.46

GERP RS

5.1

gMVP

0.85

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