rs374297889

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_021098.3(CACNA1H):c.4426G>A(p.Ala1476Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,611,752 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1476V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.93

Publications

2 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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

BP6

Variant 16-1211556-G-A is Benign according to our data. Variant chr16-1211556-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585645.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4462G>A	p.Ala1488Thr	missense_variant	Exon 23 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4387G>A	p.Ala1463Thr	missense_variant	Exon 23 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4387G>A	p.Ala1463Thr	missense_variant	Exon 23 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4426G>A	p.Ala1476Thr	missense_variant	Exon 23 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*396G>A		non_coding_transcript_exon_variant	Exon 23 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*2339G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3873G>A		non_coding_transcript_exon_variant	Exon 22 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4426G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*396G>A		3_prime_UTR_variant	Exon 23 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1 link	n.*2339G>A		3_prime_UTR_variant	Exon 23 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3873G>A		3_prime_UTR_variant	Exon 22 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000367

AC:

AN:

245158

AF XY:

0.0000448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000543

Gnomad OTH exome

AF:

0.000336

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1459534

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.0000224

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26080

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000486

AC:

AN:

1111472

Other (OTH)

AF:

0.0000332

AC:

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000113

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000332

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Apr 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jan 24, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jul 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D;.

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.7

L;.;L;L

PhyloP100

7.9

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

D;.;D;D

REVEL

Pathogenic

0.76

Sift

Benign

0.053

T;.;T;T

Sift4G

Uncertain

0.041

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.55

MVP

0.87

ClinPred

0.84

GERP RS

4.0

Varity_R

0.38

gMVP

0.79

Mutation Taster

=42/58

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