12-2688702-G-T

Position:

• chr12-2688702-G-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.6040G>T​(p.Val2014Phe) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2014I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

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 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=0.3454716).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6040G>T	p.Val2014Phe	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6040G>T	p.Val2014Phe	missense_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6040G>T	p.Val2014Phe	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6040G>T	p.Val2014Phe	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6379G>T	p.Val2127Phe	missense_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6253G>T	p.Val2085Phe	missense_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6220G>T	p.Val2074Phe	missense_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6205G>T	p.Val2069Phe	missense_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6184G>T	p.Val2062Phe	missense_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6163G>T	p.Val2055Phe	missense_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6145G>T	p.Val2049Phe	missense_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6145G>T	p.Val2049Phe	missense_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6130G>T	p.Val2044Phe	missense_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6130G>T	p.Val2044Phe	missense_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6130G>T	p.Val2044Phe	missense_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6130G>T	p.Val2044Phe	missense_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6124G>T	p.Val2042Phe	missense_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6115G>T	p.Val2039Phe	missense_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6100G>T	p.Val2034Phe	missense_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6097G>T	p.Val2033Phe	missense_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6097G>T	p.Val2033Phe	missense_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6097G>T	p.Val2033Phe	missense_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6091G>T	p.Val2031Phe	missense_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6082G>T	p.Val2028Phe	missense_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6064G>T	p.Val2022Phe	missense_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6064G>T	p.Val2022Phe	missense_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6058G>T	p.Val2020Phe	missense_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6040G>T	p.Val2014Phe	missense_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6040G>T	p.Val2014Phe	missense_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6040G>T	p.Val2014Phe	missense_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6040G>T	p.Val2014Phe	missense_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6040G>T	p.Val2014Phe	missense_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6031G>T	p.Val2011Phe	missense_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6007G>T	p.Val2003Phe	missense_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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 27, 2018

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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 2014 of the CACNA1C protein (p.Val2014Phe). The valine residue is moderately conserved and there is a small physicochemical difference between valine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	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
MetaSVM	Benign	-0.62	T
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.050	T;D;D;D;T;D;T;D;D;D;T;T;D;T;T;T;D;D;D;D;T;D;T
Polyphen		0.90, 0.63, 0.86, 0.33, 0.92, 0.93, 0.96, 0.85, 0.98, 0.97	.;P;P;P;B;P;P;D;P;P;P;D;P;D;P;.;D;P;.;.;.;D;.
Vest4		0.73
MVP		0.44
MPC		0.74
ClinPred		0.94	D
GERP RS		5.2
gMVP		0.74

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: rs199473660; hg19: chr12-2797868;