rs786205755

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS2

The NM_000719.7(CACNA1C):c.2684G>A(p.Arg895His) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,032 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: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.09

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000719.7

BP6

Variant 12-2595894-G-A is Benign according to our data. Variant chr12-2595894-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190656.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2774G>A	p.Arg925His	missense_variant	Exon 20 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2849G>A	p.Arg950His	missense_variant	Exon 21 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2774G>A	p.Arg925His	missense_variant	Exon 20 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2774G>A	p.Arg925His	missense_variant	Exon 20 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2774G>A	p.Arg925His	missense_variant	Exon 20 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2774G>A	p.Arg925His	missense_variant	Exon 20 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2759G>A	p.Arg920His	missense_variant	Exon 21 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2759G>A	p.Arg920His	missense_variant	Exon 21 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2675G>A	p.Arg892His	missense_variant	Exon 20 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2684G>A	p.Arg895His	missense_variant	Exon 20 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1291G>A		non_coding_transcript_exon_variant	Exon 18 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1291G>A		3_prime_UTR_variant	Exon 18 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461032

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000720

AC:

AN:

1111612

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jan 24, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Arg895His (CGC>CAC): c.2684 G>A in exon 20 of the CACNA1C gene (NM_000719.6). The Arg895His variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Arg895His results in a conservative amino acid substitution of of one positively charged amino acid with another at a position that is conserved across species. In silico analysis predicts Arg895His is probably damaging to the protein structure/function. The Arg895His variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with LQTS, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Arg895His is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Long QT syndrome

Uncertain:1

Jan 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 895 of the CACNA1C protein (p.Arg895His). This variant is not present in population databases (gnomAD no frequency). 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: 190656). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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

Uncertain:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autism spectrum disorder

Benign:1

Aug 13, 2021

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

CardioboostArm

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.083

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

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.93

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.67

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.

PhyloP100

5.1

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Benign

0.10

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

0.49

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, 0.87, 0.47, 0.99, 0.67, 1.0, 0.99, 0.99, 1.0, 0.99, 1.0, 1.0

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

Vest4

0.55

MutPred

0.61

.;Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);Gain of catalytic residue at D899 (P = 0);

MVP

0.92

MPC

2.2

ClinPred

0.99

GERP RS

4.9

gMVP

0.63

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over