rs121912775

Positions:

• chr12-2550020-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.1468G>A​(p.Gly490Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,605,038 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:8 O:2
• Conservation: PhyloP100: 6.48

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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=0.014768004).
• BP6: Variant 12-2550020-G-A is Benign according to our data. Variant chr12-2550020-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17634.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2, not_provided=2, Benign=3}.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000403 (585/1452762) while in subpopulation MID AF= 0.00174 (10/5756). AF 95% confidence interval is 0.000942. There are 3 homozygotes in gnomad4_exome. There are 296 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1468G>A	p.Gly490Arg	missense_variant	10/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1468G>A	p.Gly490Arg	missense_variant	10/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1468G>A	p.Gly490Arg	missense_variant	10/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1558G>A	p.Gly520Arg	missense_variant	10/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1468G>A	p.Gly490Arg	missense_variant	10/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1468G>A	p.Gly490Arg	missense_variant	10/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1633G>A	p.Gly545Arg	missense_variant	11/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1468G>A	p.Gly490Arg	missense_variant	10/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1468G>A	p.Gly490Arg	missense_variant	10/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1468G>A	p.Gly490Arg	missense_variant	10/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1558G>A	p.Gly520Arg	missense_variant	10/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1558G>A	p.Gly520Arg	missense_variant	10/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1558G>A	p.Gly520Arg	missense_variant	10/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1558G>A	p.Gly520Arg	missense_variant	10/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1468G>A	p.Gly490Arg	missense_variant	10/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1543G>A	p.Gly515Arg	missense_variant	11/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1468G>A	p.Gly490Arg	missense_variant	10/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1543G>A	p.Gly515Arg	missense_variant	11/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1468G>A	p.Gly490Arg	missense_variant	10/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1468G>A	p.Gly490Arg	missense_variant	10/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1468G>A	p.Gly490Arg	missense_variant	10/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1468G>A	p.Gly490Arg	missense_variant	10/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1468G>A	p.Gly490Arg	missense_variant	10/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1459G>A	p.Gly487Arg	missense_variant	10/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1468G>A	p.Gly490Arg	missense_variant	10/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*75G>A		non_coding_transcript_exon_variant	8/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*75G>A		3_prime_UTR_variant	8/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000665 AC: 154 AN: 231558 Hom.: 0 AF XY: 0.000670 AC XY: 84 AN XY: 125452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000590

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000403 AC: 585 AN: 1452762 Hom.: 3 Cov.: 30 AF XY: 0.000410 AC XY: 296 AN XY: 721684

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000435

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000949

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74438

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000765 Hom.: 0

Bravo AF: 0.000442

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000599 AC: 5

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4 Benign:8 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1C: PP2, PP3, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2021	Published functional studies demonstrate no damaging effect (Antzelevitch et al., 2007).; This variant is associated with the following publications: (PMID: 22581653, 17224476, 20301690, 20817017, 23414114, 24183960, 25333069, 26707467, 27711072, 25974115, 30027834, 30847666, 26582918, 28807990, 30821013, 27535533) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2015	- -

Brugada syndrome 3 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 30, 2007	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 09, 2018	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2023	Variant summary: CACNA1C c.1468G>A (p.Gly490Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 231558 control chromosomes (gnomAD). The observed variant frequency is approximately 67 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. This variant has been reported in individuals affected with Brugada syndrome, hypertrophic cardiomyopathy, and early repolarization syndrome, without strong evidence for causality (examples: Antzelevitch_2007, D'Argenio_2014, Chen_2021). Published functional studies demonstrate no damaging effect from this variant (Antzelevitch et al., 2007). The following publications have been ascertained in the context of this evaluation (PMID: 17224476, 24183960, 34222376). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Long QT syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Mar 02, 2020

- -

CACNA1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Timothy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

Aug 22, 2023

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2017

This alteration is classified as 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. -

Brugada syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.015	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	0.64	D
MutationAssessor	Uncertain	2.7	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	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	0.69
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	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.95, 0.12, 0.17, 0.98, 0.98, 0.99, 0.15, 1.0, 0.94	.;D;P;B;B;D;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;P
Vest4		0.68
MutPred		0.71		.;Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);Gain of catalytic residue at N488 (P = 0.0222);
MVP		0.91
MPC		1.4
ClinPred		0.080	T
GERP RS		5.3
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121912775; hg19: chr12-2659186;