12-2566423-C-T

Variant names:

• chr12-2566423-C-T
• rs370634418
• NM_000719.7:c.1510C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PP2 PP3 BS2

The NM_000719.7(CACNA1C):​c.1510C>T​(p.Arg504Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000503 in 1,589,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.9836
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.11

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 Uncertain_significance. Variant got 0 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 the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1600C>T	p.Arg534Cys	missense_variant, splice_region_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1675C>T	p.Arg559Cys	missense_variant, splice_region_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1600C>T	p.Arg534Cys	missense_variant, splice_region_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1600C>T	p.Arg534Cys	missense_variant, splice_region_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1600C>T	p.Arg534Cys	missense_variant, splice_region_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1600C>T	p.Arg534Cys	missense_variant, splice_region_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1585C>T	p.Arg529Cys	missense_variant, splice_region_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1585C>T	p.Arg529Cys	missense_variant, splice_region_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1501C>T	p.Arg501Cys	missense_variant, splice_region_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1510C>T	p.Arg504Cys	missense_variant, splice_region_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*117C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*117C>T		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 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: 0.00000936 AC: 2 AN: 213586 Hom.: 0 AF XY: 0.00000872 AC XY: 1 AN XY: 114722

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000777

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000487 AC: 7 AN: 1436934 Hom.: 0 Cov.: 31 AF XY: 0.00000562 AC XY: 4 AN XY: 712178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000364

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

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: 0.0000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 cysteine, which is neutral and slightly polar, at codon 504 of the CACNA1C protein (p.Arg504Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 580722). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 Uncertain:1

Oct 13, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R504C variant (also known as c.1510C>T), located in coding exon 12 of the CACNA1C gene, results from a C to T substitution at nucleotide position 1510. The arginine at codon 504 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	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	0.88
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.84	.;D;D;D;P;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.73
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
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: rs370634418; hg19: chr12-2675589;