chr12-2115290-C-T

Variant names:

• chr12-2115290-C-T
• rs121912776
• NM_000719.7:c.116C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000719.7(CACNA1C):​c.116C>T​(p.Ala39Val) variant causes a missense change. 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). Synonymous variant affecting the same amino acid position (i.e. A39A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:2
• Conservation: PhyloP100: 5.67
• Publications: 37 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836
• PP5: Variant 12-2115290-C-T is Pathogenic according to our data. Variant chr12-2115290-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17635.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.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.206C>T	p.Ala69Val	missense_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.65C>T	p.Ala22Val	missense_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.116C>T		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.94e-7 AC: 1 AN: 1440238 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 714900

African (AFR) AF: 0.00 AC: 0 AN: 32962

American (AMR) AF: 0.00 AC: 0 AN: 42212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25734

East Asian (EAS) AF: 0.00 AC: 0 AN: 38410

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103116

Other (OTH) AF: 0.00 AC: 0 AN: 59584

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: no assertion criteria provided

Submissions by phenotype

Brugada syndrome 3 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 30, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Brugada 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 as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017;PMID:22385640). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
CardioboostArm	Benign	0.025
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.022	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.84	D;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	1.0	D
MutationAssessor	Benign	0.34	.;.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.4	D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.72
Sift	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;D
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.14, 1.0, 0.98	.;.;D;.;B;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;.
Vest4		0.64, 0.65, 0.50, 0.65, 0.65, 0.56, 0.66, 0.61, 0.70, 0.58, 0.64, 0.61, 0.58, 0.65, 0.50, 0.61, 0.66, 0.63, 0.62, 0.64, 0.83
MutPred		0.55		.;Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);
MVP		0.97
MPC		2.1
ClinPred		0.98	D
GERP RS		5.8
PromoterAI		0.0059	Neutral
gMVP		0.67
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912776; hg19: chr12-2224456;