rs1453140106

Positions:

• chr12-2691105-C-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.6323C>T​(p.Ala2108Val) 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. 12/18 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31

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-AS1 (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=0.17395434).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6323C>T	p.Ala2108Val	missense_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6323C>T	p.Ala2108Val	missense_variant	47/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6323C>T	p.Ala2108Val	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6323C>T	p.Ala2108Val	missense_variant	47/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6662C>T	p.Ala2221Val	missense_variant	50/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6536C>T	p.Ala2179Val	missense_variant	48/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6503C>T	p.Ala2168Val	missense_variant	47/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6488C>T	p.Ala2163Val	missense_variant	48/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6467C>T	p.Ala2156Val	missense_variant	49/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6446C>T	p.Ala2149Val	missense_variant	47/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6428C>T	p.Ala2143Val	missense_variant	48/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6428C>T	p.Ala2143Val	missense_variant	48/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6413C>T	p.Ala2138Val	missense_variant	47/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6413C>T	p.Ala2138Val	missense_variant	47/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6413C>T	p.Ala2138Val	missense_variant	47/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6413C>T	p.Ala2138Val	missense_variant	47/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6407C>T	p.Ala2136Val	missense_variant	48/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6398C>T	p.Ala2133Val	missense_variant	48/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6383C>T	p.Ala2128Val	missense_variant	48/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6380C>T	p.Ala2127Val	missense_variant	47/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6380C>T	p.Ala2127Val	missense_variant	47/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6380C>T	p.Ala2127Val	missense_variant	47/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6374C>T	p.Ala2125Val	missense_variant	47/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6365C>T	p.Ala2122Val	missense_variant	47/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6347C>T	p.Ala2116Val	missense_variant	46/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6347C>T	p.Ala2116Val	missense_variant	46/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6341C>T	p.Ala2114Val	missense_variant	46/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6323C>T	p.Ala2108Val	missense_variant	47/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6323C>T	p.Ala2108Val	missense_variant	47/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6323C>T	p.Ala2108Val	missense_variant	47/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6323C>T	p.Ala2108Val	missense_variant	47/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6323C>T	p.Ala2108Val	missense_variant	47/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6314C>T	p.Ala2105Val	missense_variant	47/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6290C>T	p.Ala2097Val	missense_variant	46/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459776 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726000

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jun 18, 2017

This sequence change replaces alanine with valine at codon 2108 of the CACNA1C protein (p.Ala2108Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.75	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.17	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	-0.86	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.030
Sift	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.013	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.28, 0.36, 0.082, 0.037, 0.095, 0.20, 0.071, 0.24, 0.17, 1.0, 0.45	.;B;B;B;B;B;B;B;B;B;B;B;B;D;B;.;B;B;.;.;.;B;.
Vest4		0.17
MVP		0.60
MPC		0.19
ClinPred		0.70	D
GERP RS		3.6
gMVP		0.53

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: rs1453140106; hg19: chr12-2800271;