chr12-2691137-G-A

Position:

• chr12-2691137-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.6355G>A​(p.Ala2119Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000825 in 1,454,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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: 0.0000082 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.461

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 -5 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=0.08735484).
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6355G>A	p.Ala2119Thr	missense_variant	47/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6355G>A	p.Ala2119Thr	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.6355G>A	p.Ala2119Thr	missense_variant	47/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6355G>A	p.Ala2119Thr	missense_variant	47/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6694G>A	p.Ala2232Thr	missense_variant	50/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6568G>A	p.Ala2190Thr	missense_variant	48/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6535G>A	p.Ala2179Thr	missense_variant	47/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6520G>A	p.Ala2174Thr	missense_variant	48/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6499G>A	p.Ala2167Thr	missense_variant	49/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6478G>A	p.Ala2160Thr	missense_variant	47/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6460G>A	p.Ala2154Thr	missense_variant	48/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6460G>A	p.Ala2154Thr	missense_variant	48/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6445G>A	p.Ala2149Thr	missense_variant	47/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6445G>A	p.Ala2149Thr	missense_variant	47/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6445G>A	p.Ala2149Thr	missense_variant	47/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6445G>A	p.Ala2149Thr	missense_variant	47/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6439G>A	p.Ala2147Thr	missense_variant	48/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6430G>A	p.Ala2144Thr	missense_variant	48/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6415G>A	p.Ala2139Thr	missense_variant	48/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6412G>A	p.Ala2138Thr	missense_variant	47/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6412G>A	p.Ala2138Thr	missense_variant	47/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6412G>A	p.Ala2138Thr	missense_variant	47/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6406G>A	p.Ala2136Thr	missense_variant	47/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6397G>A	p.Ala2133Thr	missense_variant	47/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6379G>A	p.Ala2127Thr	missense_variant	46/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6379G>A	p.Ala2127Thr	missense_variant	46/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6373G>A	p.Ala2125Thr	missense_variant	46/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6355G>A	p.Ala2119Thr	missense_variant	47/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6355G>A	p.Ala2119Thr	missense_variant	47/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6355G>A	p.Ala2119Thr	missense_variant	47/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6355G>A	p.Ala2119Thr	missense_variant	47/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6355G>A	p.Ala2119Thr	missense_variant	47/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6346G>A	p.Ala2116Thr	missense_variant	47/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6322G>A	p.Ala2108Thr	missense_variant	46/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244546 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133384

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000907

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000825 AC: 12 AN: 1454994 Hom.: 0 Cov.: 30 AF XY: 0.00000692 AC XY: 5 AN XY: 722524

Gnomad4 AFR exome AF: 0.0000300

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: 0.00000994

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 05, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 456999). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2119 of the CACNA1C protein (p.Ala2119Thr). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2021

The p.A2119T variant (also known as c.6355G>A), located in coding exon 47 of the CACNA1C gene, results from a G to A substitution at nucleotide position 6355. The alanine at codon 2119 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.92
DEOGEN2	Benign	0.018	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.048	N
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.087	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	-1.0	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.067
Sift	Benign	0.069	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.44	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.13, 0.0020, 0.15, 0.0070, 0.24, 0.027, 0.046, 0.20, 0.0010, 0.78, 0.0030	.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.078
MVP		0.39
MPC		0.18
ClinPred		0.034	T
GERP RS		-3.3
gMVP		0.37

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: rs1470889027; hg19: chr12-2800303;