NM_021098.3:c.4378G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_021098.3(CACNA1H):c.4378G>A(p.Glu1460Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000146 in 1,612,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.85

Publications

3 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14111176).

BP6

Variant 16-1211508-G-A is Benign according to our data. Variant chr16-1211508-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 460115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35	ENST00000348261.11	NP_066921.2	O95180-1B3KQH9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1H	ENST00000348261.11 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4414G>A	p.Glu1472Lys	missense_variant	Exon 23 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4339G>A	p.Glu1447Lys	missense_variant	Exon 23 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4339G>A	p.Glu1447Lys	missense_variant	Exon 23 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4378G>A	p.Glu1460Lys	missense_variant	Exon 23 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*348G>A		non_coding_transcript_exon_variant	Exon 23 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2291G>A		non_coding_transcript_exon_variant	Exon 23 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3825G>A		non_coding_transcript_exon_variant	Exon 22 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4378G>A		non_coding_transcript_exon_variant	Exon 23 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*348G>A		3_prime_UTR_variant	Exon 23 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2291G>A		3_prime_UTR_variant	Exon 23 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*3825G>A		3_prime_UTR_variant	Exon 22 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000250

AC:

AN:

247634

AF XY:

0.000230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000140

AC:

205

AN:

1460160

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

100

AN XY:

726374

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.000112

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.000153

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00161

AC:

AN:

52106

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000819

AC:

AN:

1111698

Other (OTH)

AF:

0.000298

AC:

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41442

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.000199

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Benign:1

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;.;.;.

Eigen

Benign

0.092

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;D;D;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Benign

1.4

L;.;L;L

PhyloP100

3.8

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.8

N;.;N;N

REVEL

Uncertain

0.60

Sift

Benign

0.24

T;.;T;T

Sift4G

Benign

0.59

T;.;T;T

Polyphen

0.91

P;.;B;B

Vest4

0.61

MVP

0.82

ClinPred

0.11

GERP RS

4.2

Varity_R

0.28

gMVP

0.74

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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.

NM_021098.3:c.4378G>A

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