NM_000719.7:c.1126G>C

Variant names:

• chr12-2504854-G-C
• NM_000719.7:c.1126G>C

Variant summary

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

The NM_000719.7(CACNA1C):​c.1126G>C​(p.Val376Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,430,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 the same amino acid substitution has been previously reported as Likely benign in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V376I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86

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 the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.36006927).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1217+315G>C		intron_variant	Intron 8 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399655.6	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1216G>C	p.Val406Leu	missense_variant	Exon 8 of 50			ENSP00000507184.1
CACNA1C	ENST00000347598.9	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399638.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000683482.1	c.1117G>C	p.Val373Leu	missense_variant	Exon 8 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1126G>C	p.Val376Leu	missense_variant	Exon 8 of 46			ENSP00000507309.1
CACNA1C	ENST00000399603.6	c.1217+315G>C		intron_variant	Intron 8 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.1217+315G>C		intron_variant	Intron 8 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1217+315G>C		intron_variant	Intron 8 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1307+315G>C		intron_variant	Intron 8 of 47			ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.1217+315G>C		intron_variant	Intron 8 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1307+315G>C		intron_variant	Intron 8 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1307+315G>C		intron_variant	Intron 8 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1307+315G>C		intron_variant	Intron 8 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1307+315G>C		intron_variant	Intron 8 of 46			ENSP00000506882.1
CACNA1C	ENST00000399641.6	c.1217+315G>C		intron_variant	Intron 8 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000682835.1	c.1217+315G>C		intron_variant	Intron 8 of 46			ENSP00000507282.1
CACNA1C	ENST00000480911.6	n.1113+11468G>C		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1430806 Hom.: 0 Cov.: 27 AF XY: 0.00000280 AC XY: 2 AN XY: 713984

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: 0.00000185

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
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.072
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.3	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 0.0, 0.0060, 0.0010, 0.0030, 0.023	.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B
Vest4		0.51
MutPred		0.67		Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);Gain of catalytic residue at W371 (P = 0.0095);
MVP		0.99
MPC		1.0
ClinPred		0.20	T
GERP RS		4.3
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2614020;