rs119454949

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_021098.3(CACNA1H):c.2491G>A(p.Val831Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,612,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 9.58

Publications

9 publications found

Variant links:

Genes affected

CACNA1H (HGNC:1395): (calcium voltage-gated channel subunit alpha1 H) This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

CACNA1H Gene-Disease associations (from GenCC):

hyperaldosteronism, familial, type IV
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
childhood absence epilepsy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
epilepsy, childhood absence, susceptibility to, 6
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

CACNA1H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.2452G>A	p.Val818Met	missense_variant	Exon 11 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.2452G>A	p.Val818Met	missense_variant	Exon 11 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.2491G>A	p.Val831Met	missense_variant	Exon 11 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*404G>A		non_coding_transcript_exon_variant	Exon 11 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*1938G>A		non_coding_transcript_exon_variant	Exon 10 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.2491G>A		non_coding_transcript_exon_variant	Exon 11 of 35			ENSP00000518777.1
CACNA1H	ENST00000640028.1 link	n.*404G>A		3_prime_UTR_variant	Exon 11 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*1938G>A		3_prime_UTR_variant	Exon 10 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000121

AC:

AN:

248214

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1460542

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726572

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111754

Other (OTH)

AF:

0.00

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000316

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Jan 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 2703). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 831 of the CACNA1H protein (p.Val831Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of CACNA1H-related conditions (PMID: 12891677, 31130284). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1H protein function. Experimental studies have shown that this missense change affects CACNA1H function (PMID: 14729682, 15888660). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Epilepsy, childhood absence, susceptibility to, 6

Other:1

Mar 12, 2004

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

D;.;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.;M;M

PhyloP100

9.6

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.8

D;.;D;D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.011

D;.;D;D

Sift4G

Pathogenic

0.0010

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.88

MutPred

0.89

Loss of catalytic residue at V831 (P = 0.005);.;Loss of catalytic residue at V831 (P = 0.005);Loss of catalytic residue at V831 (P = 0.005);

MVP

0.99

ClinPred

0.97

GERP RS

3.9

Varity_R

0.64

gMVP

0.80

Mutation Taster

=31/69

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over