rs200935321

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000719.7(CACNA1C):c.1031C>A(p.Thr344Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T344I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1121C>A	p.Thr374Asn	missense_variant	Exon 7 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1022C>A	p.Thr341Asn	missense_variant	Exon 7 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1031C>A	p.Thr344Asn	missense_variant	Exon 7 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.968C>A	p.Thr323Asn	missense_variant	Exon 6 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.1031C>A		non_coding_transcript_exon_variant	Exon 7 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461792

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727186

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111934

Other (OTH)

AF:

0.00

AC:

AN:

60382

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.94

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

MutationAssessor

Uncertain

2.7

.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

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

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

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

0.97

MutPred

0.61

Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);Gain of catalytic residue at P339 (P = 0.0027);

MVP

0.95

MPC

2.4

ClinPred

0.99

GERP RS

5.1

gMVP

0.99

Mutation Taster

=4/96

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over