rs112414325

Positions:

• chr12-2688580-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.5918G>A​(p.Arg1973Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,954 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1973R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (36 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14
• Conservation: PhyloP100: 2.58

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

ACMG classification

Verdict is Benign. Variant got -19 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=0.006121576).
• BP6: Variant 12-2688580-G-A is Benign according to our data. Variant chr12-2688580-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2688580-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00195 (297/152296) while in subpopulation SAS AF= 0.018 (87/4826). AF 95% confidence interval is 0.015. There are 3 homozygotes in gnomad4. There are 170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5918G>A	p.Arg1973Gln	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5918G>A	p.Arg1973Gln	missense_variant	46/47	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1	n.333+1560C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5918G>A	p.Arg1973Gln	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.5918G>A	p.Arg1973Gln	missense_variant	46/47	1	NM_000719.7	ENSP00000382563
CACNA1C-AS1	ENST00000501371.5	n.294+1560C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00195 AC: 296 AN: 152178 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00345 AC: 857 AN: 248420 Hom.: 11 AF XY: 0.00425 AC XY: 573 AN XY: 134890

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.0126

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0153

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00414

GnomAD4 exome AF: 0.00234 AC: 3418 AN: 1461658 Hom.: 36 Cov.: 33 AF XY: 0.00276 AC XY: 2004 AN XY: 727118

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00363

GnomAD4 genome AF: 0.00195 AC: 297 AN: 152296 Hom.: 3 Cov.: 33 AF XY: 0.00228 AC XY: 170 AN XY: 74468

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00222 Hom.: 1

Bravo AF: 0.00153

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000518 AC: 2

ESP6500EA AF: 0.00218 AC: 18

ExAC AF: 0.00357 AC: 431

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00172

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	Variant summary: CACNA1C c.5918G>A affects a conserved nucleotide, resulting in amino acid change from Arg to Gln. 3/4 in-silico tools predict this variant to be benign. This variant is found in 433/121010 control chromosomes including the large and broad populations from ExAC at a frequency of 0.0035782, which is about 358 times greater than the maximal expected frequency of a pathogenic allele (0.00001) in this gene, suggesting this variant is benign. Five homozygotes were reported in ExAC. This variant has been reported in multiple LQTS and BrS patients without strong evidence for causality (eg. co-segregation studies). Clinical diagnostic labs have classified this variant as a VUS or likely benign before the large and diverse ExAC control cohorts were available. Taken together, this variant was classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	CACNA1C: PM5, BP4, BS1, BS2 -

not specified Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Dec 02, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed we consider this a variant of uncertain significance. This variant is novel. Pathogenic variants in CACNA1C are associated with Timothy syndrome and Brugada syndrome. This is a semi-conservative amino acid change with a hydrophilic basic polar Arginine replaced with a hydrophilic polar Glutamine. The variant is found in a highly conserved region of the CACNA1C gene. The reporting lab observed the variant in 2 out of 353 presumably healthy individuals of mixed ethnic background. Based on these data it is currently unclear whether this variant can cause disease, however given the presence in controls for a variant in a gene thus far only associated with quite rare diseases, it seems most likely that this variant does not cause rare Mendelian disease such as long QT syndrome. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 10, 2016	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. -

CACNA1C-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2019

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

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2016

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. -

Short QT syndrome Benign:1

Likely benign, no assertion criteria provided

clinical testing

Blueprint Genetics

Oct 14, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.83
DEOGEN2	Benign	0.0053	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0061	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	-0.94	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.51	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.59	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.032, 0.0070, 0.014, 0.0060, 0.086, 0.049, 0.083, 0.10, 0.98, 0.028	.;B;B;B;B;B;B;B;B;B;B;B;B;D;B;.;B;B;.;.;.;B;.
Vest4		0.32
MVP		0.77
MPC		0.22
ClinPred		0.013	T
GERP RS		5.0
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs112414325; hg19: chr12-2797746; COSMIC: COSV59694963; COSMIC: COSV59694963;