12-2115514-C-T

Position:

• chr12-2115514-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.340C>T​(p.Arg114Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.37

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]

CACNA1C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.340C>T	p.Arg114Trp	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.340C>T	p.Arg114Trp	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.340C>T	p.Arg114Trp	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.340C>T	p.Arg114Trp	missense_variant	2/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.430C>T	p.Arg144Trp	missense_variant	2/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.340C>T	p.Arg114Trp	missense_variant	2/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.340C>T	p.Arg114Trp	missense_variant	2/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.430C>T	p.Arg144Trp	missense_variant	2/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.340C>T	p.Arg114Trp	missense_variant	2/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.340C>T	p.Arg114Trp	missense_variant	2/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.340C>T	p.Arg114Trp	missense_variant	2/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.430C>T	p.Arg144Trp	missense_variant	2/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.430C>T	p.Arg144Trp	missense_variant	2/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.430C>T	p.Arg144Trp	missense_variant	2/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.430C>T	p.Arg144Trp	missense_variant	2/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.340C>T	p.Arg114Trp	missense_variant	2/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.340C>T	p.Arg114Trp	missense_variant	2/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.340C>T	p.Arg114Trp	missense_variant	2/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.340C>T	p.Arg114Trp	missense_variant	2/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.340C>T	p.Arg114Trp	missense_variant	2/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.340C>T	p.Arg114Trp	missense_variant	2/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.340C>T	p.Arg114Trp	missense_variant	2/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.340C>T	p.Arg114Trp	missense_variant	2/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.340C>T	p.Arg114Trp	missense_variant	2/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.340C>T	p.Arg114Trp	missense_variant	2/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.340C>T	p.Arg114Trp	missense_variant	2/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.289C>T	p.Arg97Trp	missense_variant	1/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.340C>T		non_coding_transcript_exon_variant	2/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 246874 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134430

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: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461100 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726872

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: 0.0000189

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.6	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.1	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	0.84
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	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
Polyphen		1.0	.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;.
Vest4		0.95
MutPred		0.70		Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);Gain of catalytic residue at S119 (P = 0.0031);
MVP		0.96
MPC		2.3
ClinPred		0.99	D
GERP RS		3.7
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs758229132; hg19: chr12-2224680; COSMIC: COSV59768190; COSMIC: COSV59768190;