chr12-2504487-G-A

Variant names:

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

0 publications found

Variant links:

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

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37
CACNA1C	NM_000719.7 link	c.1114-355G>A		intron_variant	Intron 7 of 46	ENST00000399655.6	NP_000710.5	Q13936-12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000406454.8 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000399617.6 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1255G>A	p.Val419Ile	missense_variant	Exon 8 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399641.6 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000682835.1 link	c.1165G>A	p.Val389Ile	missense_variant	Exon 8 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000399655.6 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1204-355G>A		intron_variant	Intron 7 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000347598.9 link	c.1114-355G>A		intron_variant	Intron 7 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1114-355G>A		intron_variant	Intron 7 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399638.5 link	c.1114-355G>A		intron_variant	Intron 7 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1114-355G>A		intron_variant	Intron 7 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1114-355G>A		intron_variant	Intron 7 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1114-355G>A		intron_variant	Intron 7 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1114-355G>A		intron_variant	Intron 7 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1114-355G>A		intron_variant	Intron 7 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1114-355G>A		intron_variant	Intron 7 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399644.5 link	c.1114-355G>A		intron_variant	Intron 7 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000683482.1 link	c.1105-355G>A		intron_variant	Intron 7 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1114-355G>A		intron_variant	Intron 7 of 45			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.1113+11101G>A		intron_variant	Intron 7 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.0045

.;.;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

0.046

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.49

T;T;T;T;T

MetaSVM

Uncertain

0.22

PhyloP100

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

GERP RS

5.0

PromoterAI

-0.018

Neutral

(source)

Mutation Taster

=23/77

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over