12-2566471-G-T

Position:

• chr12-2566471-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000719.7(CACNA1C):​c.1558G>T​(p.Ala520Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000139 in 1,443,248 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.84

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 5 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
• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1558G>T	p.Ala520Ser	missense_variant	12/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1558G>T	p.Ala520Ser	missense_variant	12/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1558G>T	p.Ala520Ser	missense_variant	12/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.1558G>T	p.Ala520Ser	missense_variant	12/47	1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000457 AC: 1 AN: 219004 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 117834

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: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443248 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715920

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: 0.00000181

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
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.63	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	0.97	D
MutationAssessor	Uncertain	2.5	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
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	Uncertain	0.66	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;D;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.052	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	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.88, 0.69, 0.94, 0.93, 0.85, 0.96, 0.98, 0.97, 0.96, 0.92, 1.0	.;P;P;P;P;P;P;D;D;D;P;D;P;P;D;P;.;D;D;.;.;.;P
Vest4		0.56
MutPred		0.52		.;Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);Gain of catalytic residue at K522 (P = 8e-04);
MVP		0.86
MPC		2.1
ClinPred		0.85	D
GERP RS		5.3
gMVP		0.88

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: rs755167125; hg19: chr12-2675637;