12-2493304-C-T

Variant names:

• chr12-2493304-C-T
• rs200935321
• NM_000719.7:c.1031C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM2 PP2 PP3_Moderate BS2

The NM_000719.7(CACNA1C):​c.1031C>T​(p.Thr344Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.91

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 1 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1121C>T	p.Thr374Ile	missense_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1022C>T	p.Thr341Ile	missense_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1031C>T	p.Thr344Ile	missense_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.968C>T	p.Thr323Ile	missense_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.1031C>T		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727186

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Long QT syndrome Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 344 of the CACNA1C protein (p.Thr344Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 191419). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.92	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	1.1	D
MutationAssessor	Benign	1.4	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.4	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	0.91
Sift	Benign	0.060	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D
Sift4G	Uncertain	0.042	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, 1.0, 0.98, 1.0	.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.97
MutPred		0.58		Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);Gain of catalytic residue at N348 (P = 0.001);
MVP		0.98
MPC		2.2
ClinPred		0.99	D
GERP RS		5.1
gMVP		0.99

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: rs200935321; hg19: chr12-2602470; COSMIC: COSV100216006;