rs80315385

Variant names:

• chr12-2504932-G-A
• rs80315385
• NM_000719.7:c.1204G>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G402R) has been classified as Uncertain significance.

• 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
• Publications: 90 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 17633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1217+393G>A		intron_variant	Intron 8 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399655.6	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1294G>A	p.Gly432Ser	missense_variant	Exon 8 of 50			ENSP00000507184.1
CACNA1C	ENST00000347598.9	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399638.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000683482.1	c.1195G>A	p.Gly399Ser	missense_variant	Exon 8 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1204G>A	p.Gly402Ser	missense_variant	Exon 8 of 46			ENSP00000507309.1
CACNA1C	ENST00000399603.6	c.1217+393G>A		intron_variant	Intron 8 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.1217+393G>A		intron_variant	Intron 8 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1217+393G>A		intron_variant	Intron 8 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1307+393G>A		intron_variant	Intron 8 of 47			ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.1217+393G>A		intron_variant	Intron 8 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1307+393G>A		intron_variant	Intron 8 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1307+393G>A		intron_variant	Intron 8 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1307+393G>A		intron_variant	Intron 8 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1307+393G>A		intron_variant	Intron 8 of 46			ENSP00000506882.1
CACNA1C	ENST00000399641.6	c.1217+393G>A		intron_variant	Intron 8 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000682835.1	c.1217+393G>A		intron_variant	Intron 8 of 46			ENSP00000507282.1
CACNA1C	ENST00000480911.6	n.1113+11546G>A		intron_variant	Intron 7 of 26	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

African (AFR) AF: 0.00 AC: 0 AN: 32614

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25904

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.00 AC: 0 AN: 85246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1074518

Other (OTH) AF: 0.00 AC: 0 AN: 58978

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Jun 07, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Timothy syndrome phenotype with or without syndactyly -

not provided Pathogenic:1

Apr 19, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has been observed in individual(s) with Timothy syndrome (PMID: 32161207, 15863612). ClinVar contains an entry for this variant (Variation ID: 17633). 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. 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. For these reasons, this variant has been classified as Pathogenic. -

Congenital long QT syndrome Other:1

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
CardioboostArm	Pathogenic	1.0
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
PhyloP100		10
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
PromoterAI		-0.0016	Neutral
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80315385; hg19: chr12-2614098;