12-2597260-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):c.2824A>T(p.Thr942Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T942A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1C
• BP4: Computational evidence support a benign effect (MetaRNN=0.11291239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.2824A>T	p.Thr942Ser	missense_variant	21/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.2824A>T	p.Thr942Ser	missense_variant	21/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2824A>T	p.Thr942Ser	missense_variant	21/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.2824A>T	p.Thr942Ser	missense_variant	21/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249212 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135202

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460238 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726506

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.0000051
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	16
Dann	Benign	0.32
DEOGEN2	Benign	0.27	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.0011	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.72	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.17	.;B;B;B;B;B;B;B;B;B;B;.;.;.;B
Vest4		0.29
MutPred		0.51		.;Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);Gain of catalytic residue at T942 (P = 2e-04);
MVP		0.70
MPC		0.95
ClinPred		0.15	T
GERP RS		5.3
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs369884505; hg19: chr12-2706426;