chr12-2690979-C-T

Position:

• chr12-2690979-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.6197C>T​(p.Ala2066Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,599,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.81

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 Likely_benign. Variant got -4 ACMG points.

• 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=0.35334295).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6197C>T	p.Ala2066Val	missense_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6197C>T	p.Ala2066Val	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.6197C>T	p.Ala2066Val	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6197C>T	p.Ala2066Val	missense_variant	47/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6536C>T	p.Ala2179Val	missense_variant	50/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6410C>T	p.Ala2137Val	missense_variant	48/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6377C>T	p.Ala2126Val	missense_variant	47/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6362C>T	p.Ala2121Val	missense_variant	48/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6341C>T	p.Ala2114Val	missense_variant	49/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6320C>T	p.Ala2107Val	missense_variant	47/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6302C>T	p.Ala2101Val	missense_variant	48/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6302C>T	p.Ala2101Val	missense_variant	48/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6287C>T	p.Ala2096Val	missense_variant	47/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6287C>T	p.Ala2096Val	missense_variant	47/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6287C>T	p.Ala2096Val	missense_variant	47/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6287C>T	p.Ala2096Val	missense_variant	47/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6281C>T	p.Ala2094Val	missense_variant	48/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6272C>T	p.Ala2091Val	missense_variant	48/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6257C>T	p.Ala2086Val	missense_variant	48/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6254C>T	p.Ala2085Val	missense_variant	47/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6254C>T	p.Ala2085Val	missense_variant	47/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6254C>T	p.Ala2085Val	missense_variant	47/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6248C>T	p.Ala2083Val	missense_variant	47/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6239C>T	p.Ala2080Val	missense_variant	47/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6221C>T	p.Ala2074Val	missense_variant	46/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6221C>T	p.Ala2074Val	missense_variant	46/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6215C>T	p.Ala2072Val	missense_variant	46/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6197C>T	p.Ala2066Val	missense_variant	47/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6197C>T	p.Ala2066Val	missense_variant	47/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6197C>T	p.Ala2066Val	missense_variant	47/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6197C>T	p.Ala2066Val	missense_variant	47/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6197C>T	p.Ala2066Val	missense_variant	47/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6188C>T	p.Ala2063Val	missense_variant	47/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6164C>T	p.Ala2055Val	missense_variant	46/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 25 AN: 1447468 Hom.: 0 Cov.: 30 AF XY: 0.0000223 AC XY: 16 AN XY: 718638

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: 0.0000208

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2022

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2066 of the CACNA1C protein (p.Ala2066Val). 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: 456994). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2024

The p.A2066V variant (also known as c.6197C>T), located in coding exon 47 of the CACNA1C gene, results from a C to T substitution at nucleotide position 6197. The alanine at codon 2066 is replaced by valine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.19	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	Uncertain	0.060	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	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, 0.94, 1.0, 0.88, 1.0, 0.99	.;D;P;D;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.64
MVP		0.81
MPC		0.75
ClinPred		1.0	D
GERP RS		4.6
gMVP		0.97

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: rs1216146146; hg19: chr12-2800145;