rs756829999

Positions:

• chr12-2679691-G-A
• chr12-2679691-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5339G>A​(p.Arg1780His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,612,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.566

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 Likely_benign. Variant got -6 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=0.2433615).
• BP6: Variant 12-2679691-G-A is Benign according to our data. Variant chr12-2679691-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 945968.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5339G>A	p.Arg1780His	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5339G>A	p.Arg1780His	missense_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5339G>A	p.Arg1780His	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5339G>A	p.Arg1780His	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5573G>A	p.Arg1858His	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5339G>A	p.Arg1780His	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5306G>A	p.Arg1769His	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5504G>A	p.Arg1835His	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5483G>A	p.Arg1828His	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5462G>A	p.Arg1821His	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5339G>A	p.Arg1780His	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5339G>A	p.Arg1780His	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5429G>A	p.Arg1810His	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5429G>A	p.Arg1810His	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5429G>A	p.Arg1810His	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5429G>A	p.Arg1810His	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5423G>A	p.Arg1808His	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5414G>A	p.Arg1805His	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5399G>A	p.Arg1800His	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5396G>A	p.Arg1799His	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5396G>A	p.Arg1799His	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5396G>A	p.Arg1799His	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5390G>A	p.Arg1797His	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5381G>A	p.Arg1794His	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5363G>A	p.Arg1788His	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5363G>A	p.Arg1788His	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5357G>A	p.Arg1786His	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5339G>A	p.Arg1780His	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5339G>A	p.Arg1780His	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5339G>A	p.Arg1780His	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5339G>A	p.Arg1780His	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5339G>A	p.Arg1780His	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5330G>A	p.Arg1777His	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5306G>A	p.Arg1769His	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000124 AC: 3 AN: 242558 Hom.: 0 AF XY: 0.0000152 AC XY: 2 AN XY: 131948

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000919

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459866 Hom.: 0 Cov.: 32 AF XY: 0.00000826 AC XY: 6 AN XY: 726072

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

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: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CACNA1C-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2022

The CACNA1C c.5339G>A variant is predicted to result in the amino acid substitution p.Arg1780His. This variant has been reported in the heterozygous state in a 57 year old asymptomatic male but diagnosed with Brugada syndrome (saddle-back type) pattern ECG at an annual health check-up (Case 4, Fukuyama et al. 2013. PubMed ID: 23575362). This variant has also been reported in a registry of variants associated with Brugada syndrome (Supplementary Table 1, Chen et al. 2019. PubMed ID: 30662450) and was reported as a variant of uncertain significance in a study of genetics associated with Brugada syndrome (Campuzano et al. 2019. PubMed ID: 30821013). This variant is reported in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-2788857-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

The p.R1780H variant (also known as c.5339G>A), located in coding exon 42 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5339. The arginine at codon 1780 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in a Japanese cohort in an individual with Brugada syndrome sign on ECG; however, the patient was asymptomatic and family history information was not available (Fukuyama M et al. Circ. J., 2013 Apr;77:1799-806). This amino acid position is poorly conserved in available vertebrate species, and histidine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	4.1
DANN	Benign	0.93
DEOGEN2	Benign	0.0039	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.24	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	-0.075	T
MutationAssessor	Benign	1.0	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.87	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.21	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.080	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010, 0.0020	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.34
MutPred		0.37		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at Y1832 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.91
MPC		0.24
ClinPred		0.044	T
GERP RS		1.4
gMVP		0.29

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: rs756829999; hg19: chr12-2788857; COSMIC: COSV59697447; COSMIC: COSV59697447;