rs764212214

Variant names:

• chr12-2682561-G-A
• rs764212214
• NM_000719.7:c.5456G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2682561-G-A
• chr12-2682561-G-C
• chr12-2682561-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1819W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.18
• Publications: 3 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1303663).
• BP6: Variant 12-2682561-G-A is Benign according to our data. Variant chr12-2682561-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456980.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5795G>A	p.Arg1932Gln	missense_variant	Exon 46 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5669G>A	p.Arg1890Gln	missense_variant	Exon 44 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5636G>A	p.Arg1879Gln	missense_variant	Exon 43 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5621G>A	p.Arg1874Gln	missense_variant	Exon 44 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 45 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5579G>A	p.Arg1860Gln	missense_variant	Exon 43 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5561G>A	p.Arg1854Gln	missense_variant	Exon 44 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5561G>A	p.Arg1854Gln	missense_variant	Exon 44 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5546G>A	p.Arg1849Gln	missense_variant	Exon 43 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5546G>A	p.Arg1849Gln	missense_variant	Exon 43 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5546G>A	p.Arg1849Gln	missense_variant	Exon 43 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5546G>A	p.Arg1849Gln	missense_variant	Exon 43 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5540G>A	p.Arg1847Gln	missense_variant	Exon 44 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5531G>A	p.Arg1844Gln	missense_variant	Exon 44 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5516G>A	p.Arg1839Gln	missense_variant	Exon 44 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5513G>A	p.Arg1838Gln	missense_variant	Exon 43 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5513G>A	p.Arg1838Gln	missense_variant	Exon 43 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5513G>A	p.Arg1838Gln	missense_variant	Exon 43 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5507G>A	p.Arg1836Gln	missense_variant	Exon 43 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5498G>A	p.Arg1833Gln	missense_variant	Exon 43 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5480G>A	p.Arg1827Gln	missense_variant	Exon 42 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5480G>A	p.Arg1827Gln	missense_variant	Exon 42 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5474G>A	p.Arg1825Gln	missense_variant	Exon 42 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5456G>A	p.Arg1819Gln	missense_variant	Exon 43 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5447G>A	p.Arg1816Gln	missense_variant	Exon 43 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5423G>A	p.Arg1808Gln	missense_variant	Exon 42 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152080 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 246452 AF XY: 0.0000150

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1459962 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726130

African (AFR) AF: 0.000120 AC: 4 AN: 33462

American (AMR) AF: 0.0000449 AC: 2 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111324

Other (OTH) AF: 0.0000663 AC: 4 AN: 60330

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74398

African (AFR) AF: 0.0000722 AC: 3 AN: 41540

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000248 AC: 3

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Sep 06, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2 -

Long QT syndrome Uncertain:1

Dec 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 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). 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

Jan 12, 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
CardioboostArm	Benign	2.6e-7
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
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	D
M_CAP	Uncertain	0.15	D
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	T
PhyloP100		3.2
PrimateAI	Benign	0.21	T
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	T
GERP RS		3.9
gMVP		0.34
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs764212214; hg19: chr12-2791727;