rs182208896

Positions:

• chr12-2685801-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.5639G>A​(p.Arg1880Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,613,700 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 1.50

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 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). GenCC has associacion of 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=0.006205976).
• BP6: Variant 12-2685801-G-A is Benign according to our data. Variant chr12-2685801-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 67555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5978G>A	p.Arg1993Gln	missense_variant	47/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5852G>A	p.Arg1951Gln	missense_variant	45/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5819G>A	p.Arg1940Gln	missense_variant	44/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5804G>A	p.Arg1935Gln	missense_variant	45/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5783G>A	p.Arg1928Gln	missense_variant	46/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5762G>A	p.Arg1921Gln	missense_variant	44/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5744G>A	p.Arg1915Gln	missense_variant	45/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5744G>A	p.Arg1915Gln	missense_variant	45/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5729G>A	p.Arg1910Gln	missense_variant	44/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5729G>A	p.Arg1910Gln	missense_variant	44/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5729G>A	p.Arg1910Gln	missense_variant	44/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5729G>A	p.Arg1910Gln	missense_variant	44/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5723G>A	p.Arg1908Gln	missense_variant	45/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5714G>A	p.Arg1905Gln	missense_variant	45/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5699G>A	p.Arg1900Gln	missense_variant	45/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5696G>A	p.Arg1899Gln	missense_variant	44/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5696G>A	p.Arg1899Gln	missense_variant	44/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5696G>A	p.Arg1899Gln	missense_variant	44/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5690G>A	p.Arg1897Gln	missense_variant	44/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5681G>A	p.Arg1894Gln	missense_variant	44/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5663G>A	p.Arg1888Gln	missense_variant	43/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5663G>A	p.Arg1888Gln	missense_variant	43/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5657G>A	p.Arg1886Gln	missense_variant	43/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5639G>A	p.Arg1880Gln	missense_variant	44/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5639G>A	p.Arg1880Gln	missense_variant	44/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5630G>A	p.Arg1877Gln	missense_variant	44/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5606G>A	p.Arg1869Gln	missense_variant	43/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000651 AC: 162 AN: 248942 Hom.: 1 AF XY: 0.000637 AC XY: 86 AN XY: 135064

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.000723

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000331 AC: 483 AN: 1461400 Hom.: 3 Cov.: 31 AF XY: 0.000344 AC XY: 250 AN XY: 727000

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0119

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000864

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000893 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.000720 AC: 6

ExAC AF: 0.000488 AC: 59

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 08, 2023	Variant summary: CACNA1C c.5639G>A (p.Arg1880Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 248942 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 65 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.5639G>A in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2016	- -

not provided Benign:2 Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CACNA1C: BP4 -
not provided, no classification provided	literature only	Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	-	This variant has been reported in the following publications (PMID:20817017). -

Brugada syndrome (shorter-than-normal QT interval) Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2018

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	-0.44	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0062	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.84	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.076
Sift	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0, 0.0020	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.20
MVP		0.42
MPC		0.22
ClinPred		0.014	T
GERP RS		1.4
gMVP		0.33

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

Other links and lift over

dbSNP: rs182208896; hg19: chr12-2794967; COSMIC: COSV59737130; COSMIC: COSV59737130;