rs202180580

Variant names:

• chr12-2504487-G-A
• rs202180580
• NM_001167623.2:c.1165G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001167623.2(CACNA1C):​c.1165G>A​(p.Val389Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_001167623.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_001167623.2	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	ENST00000399603.6	NP_001161095.1
CACNA1C	NM_000719.7	c.1114-355G>A		intron_variant	Intron 7 of 46	ENST00000399655.6	NP_000710.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 48			ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000506882.1
CACNA1C	ENST00000399641.6	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000682835.1	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47			ENSP00000507282.1
CACNA1C	ENST00000399655.6	c.1114-355G>A		intron_variant	Intron 7 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1204-355G>A		intron_variant	Intron 7 of 49			ENSP00000507184.1
CACNA1C	ENST00000347598.9	c.1114-355G>A		intron_variant	Intron 7 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1114-355G>A		intron_variant	Intron 7 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399638.5	c.1114-355G>A		intron_variant	Intron 7 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1114-355G>A		intron_variant	Intron 7 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1114-355G>A		intron_variant	Intron 7 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1114-355G>A		intron_variant	Intron 7 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1114-355G>A		intron_variant	Intron 7 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1114-355G>A		intron_variant	Intron 7 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1114-355G>A		intron_variant	Intron 7 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000683482.1	c.1105-355G>A		intron_variant	Intron 7 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1114-355G>A		intron_variant	Intron 7 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+11101G>A		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.49
DEOGEN2	Benign	0.0045	.;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	0.046
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Uncertain	0.22	D
PhyloP100		10
PROVEAN	Benign	0.18	N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.66
MutPred		0.67		Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);
MVP		0.79
ClinPred		0.84	D
GERP RS		5.0
PromoterAI		-0.018	Neutral
Mutation Taster		=23/77	disease causing

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: rs202180580; hg19: chr12-2613653;