rs58124832

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021098.3(CACNA1H):c.5612G>A(p.Arg1871Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0573 in 1,561,046 control chromosomes in the GnomAD database, including 3,036 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. R1871L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.045 ( 230 hom., cov: 34)

Exomes 𝑓: 0.059 ( 2806 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.23

Publications

20 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=0.0018953979).

BP6

Variant 16-1218376-G-A is Benign according to our data. Variant chr16-1218376-G-A is described in ClinVar as Benign. ClinVar VariationId is 585651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.072 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 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.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5627G>A	p.Arg1876Gln	missense_variant	Exon 32 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5630G>A	p.Arg1877Gln	missense_variant	Exon 32 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 32 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5627G>A	p.Arg1876Gln	missense_variant	Exon 33 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5573G>A	p.Arg1858Gln	missense_variant	Exon 33 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 32 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5555G>A	p.Arg1852Gln	missense_variant	Exon 32 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5594G>A	p.Arg1865Gln	missense_variant	Exon 32 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5612G>A	p.Arg1871Gln	missense_variant	Exon 33 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5612G>A		non_coding_transcript_exon_variant	Exon 33 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1564G>A		non_coding_transcript_exon_variant	Exon 32 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*693G>A		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3463G>A		non_coding_transcript_exon_variant	Exon 33 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5056G>A		non_coding_transcript_exon_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*586G>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*471G>A		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1224G>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*279G>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*279G>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5594G>A		non_coding_transcript_exon_variant	Exon 32 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5612G>A		non_coding_transcript_exon_variant	Exon 33 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5612G>A		non_coding_transcript_exon_variant	Exon 33 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*728G>A		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1564G>A		3_prime_UTR_variant	Exon 32 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*693G>A		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3463G>A		3_prime_UTR_variant	Exon 33 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5056G>A		3_prime_UTR_variant	Exon 31 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*586G>A		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*471G>A		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1224G>A		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*279G>A		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*279G>A		3_prime_UTR_variant	Exon 34 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*728G>A		3_prime_UTR_variant	Exon 33 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0451

AC:

6863

AN:

152190

Hom.:

229

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00914

Gnomad AMI

AF:

0.169

Gnomad AMR

AF:

0.0400

Gnomad ASJ

AF:

0.0838

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0778

Gnomad FIN

AF:

0.0488

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0645

Gnomad OTH

AF:

0.0559

GnomAD2 exomes

AF:

0.0548

AC:

9431

AN:

172182

AF XY:

0.0588

show subpopulations

Gnomad AFR exome

AF:

0.00844

Gnomad AMR exome

AF:

0.0302

Gnomad ASJ exome

AF:

0.0870

Gnomad EAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.0489

Gnomad NFE exome

AF:

0.0648

Gnomad OTH exome

AF:

0.0667

GnomAD4 exome

AF:

0.0586

AC:

82512

AN:

1408738

Hom.:

2806

Cov.:

AF XY:

0.0597

AC XY:

41527

AN XY:

695890

show subpopulations

African (AFR)

AF:

0.00741

AC:

237

AN:

31992

American (AMR)

AF:

0.0312

AC:

1146

AN:

36738

Ashkenazi Jewish (ASJ)

AF:

0.0878

AC:

2224

AN:

25338

East Asian (EAS)

AF:

0.000192

AC:

AN:

36374

South Asian (SAS)

AF:

0.0840

AC:

6692

AN:

79712

European-Finnish (FIN)

AF:

0.0503

AC:

2450

AN:

48662

Middle Eastern (MID)

AF:

0.0781

AC:

446

AN:

5708

European-Non Finnish (NFE)

AF:

0.0607

AC:

65913

AN:

1085618

Other (OTH)

AF:

0.0580

AC:

3397

AN:

58596

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

5100

10201

15301

20402

25502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2376

4752

7128

9504

11880

<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:

0.0451

AC:

6865

AN:

152308

Hom.:

230

Cov.:

AF XY:

0.0438

AC XY:

3259

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00912

AC:

379

AN:

41570

American (AMR)

AF:

0.0400

AC:

612

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0838

AC:

291

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5178

South Asian (SAS)

AF:

0.0785

AC:

379

AN:

4830

European-Finnish (FIN)

AF:

0.0488

AC:

518

AN:

10616

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0645

AC:

4387

AN:

68012

Other (OTH)

AF:

0.0549

AC:

116

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

352

704

1055

1407

1759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0569

Hom.:

440

Bravo

AF:

0.0400

TwinsUK

AF:

0.0593

AC:

220

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.00853

AC:

ESP6500EA

AF:

0.0583

AC:

489

ExAC

AF:

0.0410

AC:

4646

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 22, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28933792) -

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

Benign:1

Feb 03, 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

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.090

T;.;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.73

T;T;T;.

MetaRNN

Benign

0.0019

T;T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.7

L;.;.;.

PhyloP100

1.2

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.63

N;.;N;N

REVEL

Benign

0.28

Sift

Benign

0.49

T;.;T;T

Sift4G

Benign

0.89

T;.;T;T

Polyphen

0.16

B;.;B;B

Vest4

0.24

ClinPred

0.0021

GERP RS

1.0

Varity_R

0.068

gMVP

0.37

Mutation Taster

=100/0

polymorphism (auto)

(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