rs376628149

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_021098.3(CACNA1H):c.5989G>A(p.Ala1997Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,549,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1997S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.40

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012807757).

BP6

Variant 16-1219071-G-A is Benign according to our data. Variant chr16-1219071-G-A is described in ClinVar as Benign. ClinVar VariationId is 529696.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00042 (64/152308) while in subpopulation EAS AF = 0.00617 (32/5188). AF 95% confidence interval is 0.00449. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5989G>A	p.Ala1997Thr	missense_variant	Exon 34 of 35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1H	ENST00000348261.11 link	c.5989G>A	p.Ala1997Thr	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7
CACNA1H	ENST00000569107.6 link	c.6004G>A	p.Ala2002Thr	missense_variant	Exon 33 of 34	1		ENSP00000454990.2
CACNA1H	ENST00000711493.1 link	c.5974G>A	p.Ala1992Thr	missense_variant	Exon 33 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5971G>A	p.Ala1991Thr	missense_variant	Exon 33 of 34	1		ENSP00000455840.1
CACNA1H	ENST00000711450.1 link	c.5971G>A	p.Ala1991Thr	missense_variant	Exon 34 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5956G>A	p.Ala1986Thr	missense_variant	Exon 34 of 35	1		ENSP00000457555.2
CACNA1H	ENST00000638323.1 link	c.5950G>A	p.Ala1984Thr	missense_variant	Exon 34 of 35	5		ENSP00000492267.1
CACNA1H	ENST00000562079.6 link	c.5938G>A	p.Ala1980Thr	missense_variant	Exon 33 of 34	1		ENSP00000454581.2
CACNA1H	ENST00000711438.1 link	c.5932G>A	p.Ala1978Thr	missense_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5989G>A	p.Ala1997Thr	missense_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5938G>A	p.Ala1980Thr	missense_variant	Exon 33 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5911G>A	p.Ala1971Thr	missense_variant	Exon 34 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5989G>A	p.Ala1997Thr	missense_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2 link	n.5989G>A		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1908G>A		non_coding_transcript_exon_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1037G>A		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3807G>A		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5433G>A		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*930G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*848G>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1568G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*656G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*623G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5938G>A		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5989G>A		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5956G>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1105G>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1908G>A		3_prime_UTR_variant	Exon 33 of 34	5		ENSP00000492650.2
CACNA1H	ENST00000639478.1 link	n.*1037G>A		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1
CACNA1H	ENST00000640028.1 link	n.*3807G>A		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1
CACNA1H	ENST00000711442.1 link	n.*5433G>A		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*930G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*848G>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1568G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*656G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*623G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*1105G>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711456.1 link	c.5887+420G>A		intron_variant	Intron 33 of 33			ENSP00000518769.1

Frequencies

GnomAD3 genomes

AF:

0.000421

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00615

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000659

AC:

100

AN:

151836

AF XY:

0.000679

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00620

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00140

GnomAD4 exome

AF:

0.000210

AC:

294

AN:

1397448

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

167

AN XY:

689272

show subpopulations

African (AFR)

AF:

0.0000633

AC:

AN:

31598

American (AMR)

AF:

0.000168

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25138

East Asian (EAS)

AF:

0.00277

AC:

AN:

35736

South Asian (SAS)

AF:

0.00120

AC:

AN:

79212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47660

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000287

AC:

AN:

1078762

Other (OTH)

AF:

0.00105

AC:

AN:

57964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000420

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41552

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00617

AC:

AN:

5188

South Asian (SAS)

AF:

0.00311

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000178

Hom.:

Bravo

AF:

0.000329

ExAC

AF:

0.000300

AC:

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Feb 02, 2025

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

0.074

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

0.17

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.12

T;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.38

T;T;T;.

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.00090

MutationAssessor

Benign

0.77

N;.;.;.

PhyloP100

-1.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.53

N;.;N;N

REVEL

Uncertain

0.30

Sift

Benign

0.44

T;.;T;T

Sift4G

Benign

0.57

T;.;T;T

Polyphen

0.0010

B;.;B;B

Vest4

0.035

MVP

0.80

ClinPred

0.0059

GERP RS

-3.9

Varity_R

0.056

gMVP

0.21

Mutation Taster

=97/3

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