12-2653847-G-T

Variant names:

• chr12-2653847-G-T
• rs1555968941
• NM_000719.7:c.4087G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PM5 PP3 PP5

The NM_000719.7(CACNA1C):​c.4087G>T​(p.Val1363Leu) 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 (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1363M) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.99
• Publications: 0 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 10 ACMG points.

• PS1: Transcript NM_000719.7 (CACNA1C) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-2653847-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 450063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.812
• PP5: Variant 12-2653847-G-T is Pathogenic according to our data. Variant chr12-2653847-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1164022.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4321G>T	p.Val1441Leu	missense_variant	Exon 35 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4054G>T	p.Val1352Leu	missense_variant	Exon 32 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4252G>T	p.Val1418Leu	missense_variant	Exon 34 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4231G>T	p.Val1411Leu	missense_variant	Exon 35 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4153G>T	p.Val1385Leu	missense_variant	Exon 33 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 33 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 33 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 33 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4177G>T	p.Val1393Leu	missense_variant	Exon 33 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4171G>T	p.Val1391Leu	missense_variant	Exon 34 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4162G>T	p.Val1388Leu	missense_variant	Exon 34 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4147G>T	p.Val1383Leu	missense_variant	Exon 34 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4138G>T	p.Val1380Leu	missense_variant	Exon 33 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4129G>T	p.Val1377Leu	missense_variant	Exon 33 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4054G>T	p.Val1352Leu	missense_variant	Exon 32 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4054G>T	p.Val1352Leu	missense_variant	Exon 32 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4048G>T	p.Val1350Leu	missense_variant	Exon 32 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4087G>T	p.Val1363Leu	missense_variant	Exon 33 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4078G>T	p.Val1360Leu	missense_variant	Exon 33 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4054G>T	p.Val1352Leu	missense_variant	Exon 32 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Timothy syndrome Pathogenic:1

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.81	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	Benign	2.0	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.65, 1.0, 0.96, 1.0, 1.0, 1.0, 0.76, 1.0, 0.50, 0.97, 0.96	.;P;D;D;D;P;D;D;D;P;D;P;P;D;P;.;D;P;.;.;.;D;.
Vest4		0.63
MutPred		0.64		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at V1416 (P = 5e-04);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.91
MPC		2.2
ClinPred		0.99	D
GERP RS		4.6
gMVP		0.98
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555968941; hg19: chr12-2763013;