rs200400235

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_021098.3(CACNA1H):c.4045G>A(p.Ala1349Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,600,820 control chromosomes in the GnomAD database, including 1 homozygotes. 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. A1349V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000064 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.17

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.035609752).

BP6

Variant 16-1210793-G-A is Benign according to our data. Variant chr16-1210793-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529637.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000984 (15/152364) while in subpopulation EAS AF = 0.00289 (15/5192). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.4006G>A	p.Ala1336Thr	missense_variant	Exon 21 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.4006G>A	p.Ala1336Thr	missense_variant	Exon 21 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4045G>A	p.Ala1349Thr	missense_variant	Exon 21 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*15G>A		non_coding_transcript_exon_variant	Exon 21 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*1958G>A		non_coding_transcript_exon_variant	Exon 21 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3492G>A		non_coding_transcript_exon_variant	Exon 20 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4045G>A		non_coding_transcript_exon_variant	Exon 21 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*15G>A		3_prime_UTR_variant	Exon 21 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000640028.1 link	n.*1958G>A		3_prime_UTR_variant	Exon 21 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*3492G>A		3_prime_UTR_variant	Exon 20 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00288

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:

0.000290

AC:

AN:

237694

AF XY:

0.000268

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.0000642

AC:

AN:

1448456

Hom.:

Cov.:

AF XY:

0.0000652

AC XY:

AN XY:

721102

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00229

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40690

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111588

Other (OTH)

AF:

0.0000332

AC:

AN:

60262

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

Age Distribution

Exome Het

Exome Hom

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:

0.0000984

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41588

American (AMR)

AF:

0.00

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00289

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

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:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000154

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.000281

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 08, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34098317, 37593999) -

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

Benign:1

Oct 18, 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

Uncertain

0.45

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;.

M_CAP

Pathogenic

0.49

MetaRNN

Benign

0.036

T;T;T;T

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

M;.;M;M

PhyloP100

3.2

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.9

D;.;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;.;D;D

Sift4G

Uncertain

0.0040

D;.;D;D

Polyphen

0.99

D;.;D;D

Vest4

0.87

MVP

0.96

ClinPred

0.14

GERP RS

4.2

Varity_R

0.58

gMVP

0.79

Mutation Taster

=52/48

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