rs794727587

Variant names:

• chr12-2665600-C-G
• rs794727587
• NM_000719.7:c.4418C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_000719.7(CACNA1C):​c.4418C>G​(p.Ala1473Gly) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1473P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.91
• Publications: 29 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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-2665599-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1700075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-2665600-C-G is Pathogenic according to our data. Variant chr12-2665600-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 196966.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.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4652C>G	p.Ala1551Gly	missense_variant	Exon 38 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4385C>G	p.Ala1462Gly	missense_variant	Exon 35 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4583C>G	p.Ala1528Gly	missense_variant	Exon 37 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4562C>G	p.Ala1521Gly	missense_variant	Exon 38 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4484C>G	p.Ala1495Gly	missense_variant	Exon 36 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4508C>G	p.Ala1503Gly	missense_variant	Exon 36 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4508C>G	p.Ala1503Gly	missense_variant	Exon 36 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4508C>G	p.Ala1503Gly	missense_variant	Exon 36 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4508C>G	p.Ala1503Gly	missense_variant	Exon 36 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4502C>G	p.Ala1501Gly	missense_variant	Exon 37 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4493C>G	p.Ala1498Gly	missense_variant	Exon 37 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4478C>G	p.Ala1493Gly	missense_variant	Exon 37 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4469C>G	p.Ala1490Gly	missense_variant	Exon 36 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4460C>G	p.Ala1487Gly	missense_variant	Exon 36 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4385C>G	p.Ala1462Gly	missense_variant	Exon 35 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4385C>G	p.Ala1462Gly	missense_variant	Exon 35 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4379C>G	p.Ala1460Gly	missense_variant	Exon 35 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4418C>G	p.Ala1473Gly	missense_variant	Exon 36 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4409C>G	p.Ala1470Gly	missense_variant	Exon 36 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4385C>G	p.Ala1462Gly	missense_variant	Exon 35 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome Pathogenic:1 Other:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Criteria: PS2_Strong, PS3_Moderate, PM2, PP3 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Severe Timothy syndrome phenotype -

not provided Pathogenic:1

Apr 24, 2015

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;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;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.024	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.016	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, 1.0, 1.0, 1.0, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.87
MutPred		0.71		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at V1520 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.2
ClinPred		0.99	D
GERP RS		4.9
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794727587; hg19: chr12-2774766;