12-2115304-C-T

Position:

• chr12-2115304-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.130C>T​(p.Pro44Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91

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 2 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38070005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.130C>T	p.Pro44Ser	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.130C>T	p.Pro44Ser	missense_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.130C>T	p.Pro44Ser	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.130C>T	p.Pro44Ser	missense_variant	2/47	1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000475 AC: 1 AN: 210696 Hom.: 0 AF XY: 0.00000866 AC XY: 1 AN XY: 115446

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: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1441832 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 715902

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.38	T;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	0.57	D
MutationAssessor	Benign	1.4	.;.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
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	0.80	T
PROVEAN	Pathogenic	-6.8	D;N;N;N;N;N;D;N;N;N;N;N;D;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.010	D;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0050, 0.14, 0.33, 0.51, 0.026, 0.57, 0.016	.;.;B;.;B;B;B;B;P;P;B;B;P;P;B;B;P;.;P;P;.;.;.;.
Vest4		0.38, 0.43, 0.38, 0.42, 0.42, 0.41, 0.42, 0.40, 0.40, 0.43, 0.41, 0.41, 0.42, 0.39, 0.42, 0.40, 0.46, 0.41, 0.41
MutPred		0.44		.;Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);Gain of catalytic residue at T45 (P = 0.0054);
MVP		0.75
MPC		1.3
ClinPred		0.38	T
GERP RS		5.8
gMVP		0.73

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: rs1057518456; hg19: chr12-2224470; COSMIC: COSV59707096;