NM_021098.3:c.926G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_021098.3(CACNA1H):c.926G>A(p.Arg309His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000425 in 1,601,730 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R309C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.68

Publications

4 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10715234).

BP6

Variant 16-1200378-G-A is Benign according to our data. Variant chr16-1200378-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 460194.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000204 (31/152324) while in subpopulation AFR AF = 0.000722 (30/41574). AF 95% confidence interval is 0.000518. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.887G>A	p.Arg296His	missense_variant	Exon 7 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.887G>A	p.Arg296His	missense_variant	Exon 7 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.926G>A	p.Arg309His	missense_variant	Exon 7 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*373G>A		non_coding_transcript_exon_variant	Exon 6 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.926G>A		non_coding_transcript_exon_variant	Exon 7 of 35			ENSP00000518777.1
CACNA1H	ENST00000711442.1 link	n.*373G>A		3_prime_UTR_variant	Exon 6 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000483

AC:

AN:

227840

AF XY:

0.0000480

show subpopulations

Gnomad AFR exome

AF:

0.000603

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000599

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000352

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1449406

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

720218

show subpopulations

African (AFR)

AF:

0.000844

AC:

AN:

33194

American (AMR)

AF:

0.0000231

AC:

AN:

43374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25884

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39142

South Asian (SAS)

AF:

0.00

AC:

AN:

85322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49842

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106932

Other (OTH)

AF:

0.0000500

AC:

AN:

59960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.000204

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41574

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00187

Hom.:

Bravo

AF:

0.000215

ESP6500AA

AF:

0.000990

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000834

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1H c.926G>A (p.Arg309His) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4.8e-05 in 227840 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1H causing Idiopathic Generalized Epilepsy, allowing no conclusion about variant significance. c.926G>A has been observed in individual(s) affected with Idiopathic Generalized Epilepsy. These report(s) do not provide unequivocal conclusions about association of the variant with Idiopathic Generalized Epilepsy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 36539902). ClinVar contains an entry for this variant (Variation ID: 460194). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.926G>A (p.R309H) alteration is located in exon 7 (coding exon 6) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 926, causing the arginine (R) at amino acid position 309 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jun 26, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.098

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

D;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.88

D;D;D;.

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.1

M;.;M;M

PhyloP100

1.7

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.8

N;.;N;N

REVEL

Uncertain

0.39

Sift

Benign

0.039

D;.;D;D

Sift4G

Uncertain

0.053

T;.;T;T

Polyphen

0.99

D;.;D;D

Vest4

0.39

MVP

0.92

ClinPred

0.28

GERP RS

4.4

Varity_R

0.061

gMVP

0.79

Mutation Taster

=93/7

polymorphism

(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