rs370634418

chr12-2566423-C-Achr12-2566423-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000719.7(CACNA1C):c.1510C>A(p.Arg504Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000696 in 1,436,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R504C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.9901
• Clinical Significance: Not reported in ClinVar
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1C
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.1510C>A	p.Arg504Ser	missense_variant, splice_region_variant	12/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.1510C>A	p.Arg504Ser	missense_variant, splice_region_variant	12/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1510C>A	p.Arg504Ser	missense_variant, splice_region_variant	12/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.1510C>A	p.Arg504Ser	missense_variant, splice_region_variant	12/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000468 AC: 1 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000106

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436934 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	36
Dann	Uncertain	1.0
DEOGEN2	Benign	0.074	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.88	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	0.87	D
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;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.3	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	0.78
Sift	Benign	0.043	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.99, 0.99, 1.0, 1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.82
MutPred		0.46		.;Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);Gain of catalytic residue at K501 (P = 0.009);
MVP		0.98
MPC		2.4
ClinPred		0.97	D
GERP RS		5.3
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.93		Position offset: 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;