chr12-2664926-C-T

Position:

• chr12-2664926-C-T

Variant summary

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

The ENST00000399655.6(CACNA1C):​c.4334C>T​(p.Thr1445Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C ENST00000399655.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.631

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 1 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=0.10169023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4568C>T	p.Thr1523Ile	missense_variant	37/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4334C>T	p.Thr1445Ile	missense_variant	35/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4301C>T	p.Thr1434Ile	missense_variant	34/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4499C>T	p.Thr1500Ile	missense_variant	36/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4478C>T	p.Thr1493Ile	missense_variant	37/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4400C>T	p.Thr1467Ile	missense_variant	35/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4334C>T	p.Thr1445Ile	missense_variant	35/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4334C>T	p.Thr1445Ile	missense_variant	35/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4424C>T	p.Thr1475Ile	missense_variant	35/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4424C>T	p.Thr1475Ile	missense_variant	35/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4424C>T	p.Thr1475Ile	missense_variant	35/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4424C>T	p.Thr1475Ile	missense_variant	35/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4418C>T	p.Thr1473Ile	missense_variant	36/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4409C>T	p.Thr1470Ile	missense_variant	36/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4394C>T	p.Thr1465Ile	missense_variant	36/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4385C>T	p.Thr1462Ile	missense_variant	35/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4376C>T	p.Thr1459Ile	missense_variant	35/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4301C>T	p.Thr1434Ile	missense_variant	34/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4301C>T	p.Thr1434Ile	missense_variant	34/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4295C>T	p.Thr1432Ile	missense_variant	34/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4334C>T	p.Thr1445Ile	missense_variant	35/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4334C>T	p.Thr1445Ile	missense_variant	35/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4325C>T	p.Thr1442Ile	missense_variant	35/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4301C>T	p.Thr1434Ile	missense_variant	34/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2017

This sequence change replaces threonine with isoleucine at codon 1445 of the CACNA1C protein (p.Thr1445Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1C-related disease. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.067	N
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.10	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	0.14	D
MutationAssessor	Benign	1.0	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.94	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.24
Sift	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.26, 0.015, 0.040, 0.49, 0.21, 0.88, 0.27, 0.13, 0.14, 0.60, 0.96	.;B;B;B;B;P;B;B;B;P;B;B;B;P;B;.;B;B;.;.;.;D;.
Vest4		0.26
MutPred		0.50		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1497 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.47
MPC		1.1
ClinPred		0.13	T
GERP RS		3.2
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: rs1555994788; hg19: chr12-2774092;