rs148651456

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021098.3(CACNA1H):c.5113G>A(p.Ala1705Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00716 in 1,611,068 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1705A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0073 ( 37 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 9.78

Publications

17 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011093318).

BP6

Variant 16-1215315-G-A is Benign according to our data. Variant chr16-1215315-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0057 (869/152328) while in subpopulation NFE AF = 0.00858 (584/68026). AF 95% confidence interval is 0.00801. There are 5 homozygotes in GnomAd4. There are 374 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 869 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 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.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5128G>A	p.Ala1710Thr	missense_variant	Exon 28 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5131G>A	p.Ala1711Thr	missense_variant	Exon 28 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5095G>A	p.Ala1699Thr	missense_variant	Exon 28 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5128G>A	p.Ala1710Thr	missense_variant	Exon 29 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5074G>A	p.Ala1692Thr	missense_variant	Exon 29 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5095G>A	p.Ala1699Thr	missense_variant	Exon 28 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5056G>A	p.Ala1686Thr	missense_variant	Exon 28 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5095G>A	p.Ala1699Thr	missense_variant	Exon 28 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 29 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5113G>A		non_coding_transcript_exon_variant	Exon 29 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1065G>A		non_coding_transcript_exon_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*194G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2964G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4557G>A		non_coding_transcript_exon_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5095G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5095G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*114G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5113G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5113G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5095G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5113G>A		non_coding_transcript_exon_variant	Exon 29 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5113G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*114G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1065G>A		3_prime_UTR_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*194G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2964G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4557G>A		3_prime_UTR_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*114G>A		3_prime_UTR_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*114G>A		3_prime_UTR_variant	Exon 28 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.00570

AC:

868

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.00662

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00858

Gnomad OTH

AF:

0.00669

GnomAD2 exomes

AF:

0.00556

AC:

1356

AN:

243960

AF XY:

0.00551

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.00424

Gnomad ASJ exome

AF:

0.00871

Gnomad EAS exome

AF:

0.0000562

Gnomad FIN exome

AF:

0.00557

Gnomad NFE exome

AF:

0.00835

Gnomad OTH exome

AF:

0.00941

GnomAD4 exome

AF:

0.00731

AC:

10664

AN:

1458740

Hom.:

Cov.:

AF XY:

0.00711

AC XY:

5161

AN XY:

725390

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33436

American (AMR)

AF:

0.00508

AC:

226

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.00891

AC:

232

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.000280

AC:

AN:

85786

European-Finnish (FIN)

AF:

0.00595

AC:

311

AN:

52248

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00844

AC:

9377

AN:

1111044

Other (OTH)

AF:

0.00718

AC:

433

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

615

1231

1846

2462

3077

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00570

AC:

869

AN:

152328

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

374

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41576

American (AMR)

AF:

0.00850

AC:

130

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00442

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00858

AC:

584

AN:

68026

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00696

Hom.:

Bravo

AF:

0.00630

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00161

AC:

ESP6500EA

AF:

0.00925

AC:

ExAC

AF:

0.00554

AC:

670

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1H: BS2 -

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2019

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jan 31, 2023

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 29, 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

0.23

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;.;.

Eigen

Uncertain

0.31

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Pathogenic

0.92

MutationAssessor

Benign

1.4

L;.;.;.

PhyloP100

9.8

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.9

D;.;D;D

REVEL

Uncertain

0.61

Sift

Benign

0.060

T;.;T;T

Sift4G

Uncertain

0.039

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.64

MVP

0.95

ClinPred

0.022

GERP RS

4.0

Varity_R

0.32

gMVP

0.69

Mutation Taster

=83/17

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