rs764212214

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000719.7(CACNA1C):c.5456G>A(p.Arg1819Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,612,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.18

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 Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ: 6.4654 (greater than the threshold 3.09). Trascript score misZ: 7.2674 (greater than threshold 3.09). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the gene with 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.1303663).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5795G>A	p.Arg1932Gln	missense_variant	46/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.5669G>A	p.Arg1890Gln	missense_variant	44/48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5636G>A	p.Arg1879Gln	missense_variant	43/47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.5621G>A	p.Arg1874Gln	missense_variant	44/48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5600G>A	p.Arg1867Gln	missense_variant	45/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5579G>A	p.Arg1860Gln	missense_variant	43/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5561G>A	p.Arg1854Gln	missense_variant	44/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5561G>A	p.Arg1854Gln	missense_variant	44/48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5546G>A	p.Arg1849Gln	missense_variant	43/47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5546G>A	p.Arg1849Gln	missense_variant	43/47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5546G>A	p.Arg1849Gln	missense_variant	43/47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5546G>A	p.Arg1849Gln	missense_variant	43/47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5540G>A	p.Arg1847Gln	missense_variant	44/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5531G>A	p.Arg1844Gln	missense_variant	44/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5516G>A	p.Arg1839Gln	missense_variant	44/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5513G>A	p.Arg1838Gln	missense_variant	43/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5513G>A	p.Arg1838Gln	missense_variant	43/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5513G>A	p.Arg1838Gln	missense_variant	43/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5507G>A	p.Arg1836Gln	missense_variant	43/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5498G>A	p.Arg1833Gln	missense_variant	43/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5480G>A	p.Arg1827Gln	missense_variant	42/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5480G>A	p.Arg1827Gln	missense_variant	42/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5474G>A	p.Arg1825Gln	missense_variant	42/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5456G>A	p.Arg1819Gln	missense_variant	43/47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5447G>A	p.Arg1816Gln	missense_variant	43/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5423G>A	p.Arg1808Gln	missense_variant	42/46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000203

AC:

AN:

246452

Hom.:

AF XY:

0.0000150

AC XY:

AN XY:

133674

show subpopulations

Gnomad AFR exome

AF:

0.0000654

Gnomad AMR exome

AF:

0.0000584

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000660

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1459962

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726130

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Bravo

AF:

0.0000264

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 06, 2024

PP2 -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2022

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1819 of the CACNA1C protein (p.Arg1819Gln). This variant is present in population databases (rs764212214, 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: 456980). 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) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2022

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

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.93

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

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

MetaSVM

Uncertain

-0.15

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.2

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

REVEL

Benign

0.28

Sift

Benign

0.12

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

Sift4G

Benign

0.56

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

Polyphen

0.024, 0.0, 0.018, 0.0010, 0.014, 0.0020, 0.011

.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.

Vest4

0.12

MVP

0.57

MPC

0.22

ClinPred

0.15

GERP RS

3.9

gMVP

0.34

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