rs80315385

Positions:

• chr12-2504932-G-A
• chr12-2504932-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_Moderate PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000719.7(CACNA1C):​c.1204G>A​(p.Gly402Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript NM_000719.7 (CACNA1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant 12-2504932-G-A is Pathogenic according to our data. Variant chr12-2504932-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1204G>A	p.Gly402Ser	missense_variant	8/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1217+393G>A		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399655.6	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1294G>A	p.Gly432Ser	missense_variant	8/50			ENSP00000507184.1
CACNA1C	ENST00000347598.9	c.1204G>A	p.Gly402Ser	missense_variant	8/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1204G>A	p.Gly402Ser	missense_variant	8/48	1		ENSP00000329877.7
CACNA1C	ENST00000399638.5	c.1204G>A	p.Gly402Ser	missense_variant	8/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1204G>A	p.Gly402Ser	missense_variant	8/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1204G>A	p.Gly402Ser	missense_variant	8/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1204G>A	p.Gly402Ser	missense_variant	8/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1204G>A	p.Gly402Ser	missense_variant	8/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1204G>A	p.Gly402Ser	missense_variant	8/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1204G>A	p.Gly402Ser	missense_variant	8/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.1204G>A	p.Gly402Ser	missense_variant	8/47	1		ENSP00000382552.1
CACNA1C	ENST00000683482.1	c.1195G>A	p.Gly399Ser	missense_variant	8/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1204G>A	p.Gly402Ser	missense_variant	8/46			ENSP00000507309.1
CACNA1C	ENST00000399603.6	c.1217+393G>A		intron_variant		5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.1217+393G>A		intron_variant		5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1217+393G>A		intron_variant		5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1307+393G>A		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.1217+393G>A		intron_variant		5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1307+393G>A		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1307+393G>A		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1307+393G>A		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1307+393G>A		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000399641.6	c.1217+393G>A		intron_variant		1		ENSP00000382549.1
CACNA1C	ENST00000682835.1	c.1217+393G>A		intron_variant				ENSP00000507282.1
CACNA1C	ENST00000480911.6	n.1113+11546G>A		intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1420430 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 709186

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 07, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	Timothy syndrome phenotype with or without syndactyly -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21685391, 15863612, 25691416, 23979604, 24773605, 28807990, 28341588, 30513141, 29032884, 32161207) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 30, 2020

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 expected to disrupt CACNA1C protein function. This variant has been observed in individual(s) with Timothy syndrome (PMID: 32161207, 15863612). ClinVar contains an entry for this variant (Variation ID: 17633). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 402 of the CACNA1C protein (p.Gly402Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Congenital long QT syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported in the following publications (PMID:15863612;PMID:21685391). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99	.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D
Vest4		0.95
MutPred		0.75		Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);Gain of catalytic residue at G402 (P = 2e-04);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		5.3
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs80315385; hg19: chr12-2614098;