rs765111782

Positions:

• chr12-2585488-G-A
• chr12-2585488-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_000719.7(CACNA1C):​c.2452G>A​(p.Ala818Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,559,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -7 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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=0.03137636).
• BS2: High AC in GnomAdExome4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2452G>A	p.Ala818Thr	missense_variant	17/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2452G>A	p.Ala818Thr	missense_variant	17/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2452G>A	p.Ala818Thr	missense_variant	17/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2542G>A	p.Ala848Thr	missense_variant	17/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2452G>A	p.Ala818Thr	missense_variant	17/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2452G>A	p.Ala818Thr	missense_variant	17/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2617G>A	p.Ala873Thr	missense_variant	18/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2452G>A	p.Ala818Thr	missense_variant	17/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2452G>A	p.Ala818Thr	missense_variant	17/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2452G>A	p.Ala818Thr	missense_variant	17/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2542G>A	p.Ala848Thr	missense_variant	17/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2542G>A	p.Ala848Thr	missense_variant	17/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2542G>A	p.Ala848Thr	missense_variant	17/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2542G>A	p.Ala848Thr	missense_variant	17/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2452G>A	p.Ala818Thr	missense_variant	17/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2527G>A	p.Ala843Thr	missense_variant	18/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2452G>A	p.Ala818Thr	missense_variant	17/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2527G>A	p.Ala843Thr	missense_variant	18/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2452G>A	p.Ala818Thr	missense_variant	17/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2452G>A	p.Ala818Thr	missense_variant	17/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2452G>A	p.Ala818Thr	missense_variant	17/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2452G>A	p.Ala818Thr	missense_variant	17/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2452G>A	p.Ala818Thr	missense_variant	17/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2443G>A	p.Ala815Thr	missense_variant	17/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2452G>A	p.Ala818Thr	missense_variant	17/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1059G>A		non_coding_transcript_exon_variant	15/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1059G>A		3_prime_UTR_variant	15/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000199 AC: 28 AN: 1407508 Hom.: 0 Cov.: 31 AF XY: 0.0000187 AC XY: 13 AN XY: 695184

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: 0.0000253

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000240

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74456

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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: 0.00000378

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

Jan 19, 2024

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 818 of the CACNA1C protein (p.Ala818Thr). 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: 456954). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	15
DANN	Benign	0.58
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.46	N
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.031	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	-0.42	T
MutationAssessor	Benign	0.020	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.2	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0, 0.0020	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;B;.;B
Vest4		0.040
MutPred		0.27		.;Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);Gain of catalytic residue at P816 (P = 2e-04);
MVP		0.39
MPC		1.0
ClinPred		0.12	T
GERP RS		2.5
gMVP		0.23

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: rs765111782; hg19: chr12-2694654;