rs1054644

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.6179G>A(p.Arg2060His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,483,932 control chromosomes in the GnomAD database, including 13,314 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. R2060C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.094 ( 920 hom., cov: 35)

Exomes 𝑓: 0.13 ( 12394 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.429

Publications

22 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=0.0051501095).

BP6

Variant 16-1220111-G-A is Benign according to our data. Variant chr16-1220111-G-A is described in ClinVar as Benign. ClinVar VariationId is 96015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6179G>A	p.Arg2060His	missense_variant	Exon 35 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.6179G>A	p.Arg2060His	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.6194G>A	p.Arg2065His	missense_variant	Exon 34 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.6164G>A	p.Arg2055His	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6161G>A	p.Arg2054His	missense_variant	Exon 34 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.6161G>A	p.Arg2054His	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6146G>A	p.Arg2049His	missense_variant	Exon 35 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.6140G>A	p.Arg2047His	missense_variant	Exon 35 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.6128G>A	p.Arg2043His	missense_variant	Exon 34 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.6122G>A	p.Arg2041His	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000637236.3 link	n.*2098G>A		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1227G>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3997G>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5623G>A		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1120G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1038G>A		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1758G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*846G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*813G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*93G>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6179G>A		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6146G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1295G>A		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1 link	c.*93G>A		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*93G>A		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2098G>A		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1227G>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3997G>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5623G>A		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1120G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1038G>A		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1758G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*846G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*813G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*93G>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1295G>A		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711482.1 link	c.6122-50G>A		intron_variant	Intron 35 of 35			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.6071-50G>A		intron_variant	Intron 34 of 34			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.6044-50G>A		intron_variant	Intron 35 of 35			ENSP00000518768.1
CACNA1H	ENST00000621827.2 link	n.6121+58G>A		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

AF:

0.0942

AC:

14328

AN:

152106

Hom.:

922

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.0934

Gnomad AMR

AF:

0.0737

Gnomad ASJ

AF:

0.0848

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.251

Gnomad FIN

AF:

0.0985

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.134

Gnomad OTH

AF:

0.0952

GnomAD2 exomes

AF:

0.108

AC:

14677

AN:

135794

AF XY:

0.116

show subpopulations

Gnomad AFR exome

AF:

0.0227

Gnomad AMR exome

AF:

0.0448

Gnomad ASJ exome

AF:

0.0775

Gnomad EAS exome

AF:

0.0216

Gnomad FIN exome

AF:

0.0990

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

AF:

0.130

AC:

173665

AN:

1331708

Hom.:

12394

Cov.:

AF XY:

0.133

AC XY:

86695

AN XY:

651552

show subpopulations

African (AFR)

AF:

0.0218

AC:

591

AN:

27058

American (AMR)

AF:

0.0507

AC:

1442

AN:

28440

Ashkenazi Jewish (ASJ)

AF:

0.0887

AC:

1770

AN:

19946

East Asian (EAS)

AF:

0.0165

AC:

549

AN:

33266

South Asian (SAS)

AF:

0.235

AC:

15068

AN:

64170

European-Finnish (FIN)

AF:

0.107

AC:

5105

AN:

47864

Middle Eastern (MID)

AF:

0.0922

AC:

488

AN:

5292

European-Non Finnish (NFE)

AF:

0.135

AC:

142036

AN:

1050904

Other (OTH)

AF:

0.121

AC:

6616

AN:

54768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

8774

17548

26323

35097

43871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5340

10680

16020

21360

26700

<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:

0.0941

AC:

14323

AN:

152224

Hom.:

920

Cov.:

AF XY:

0.0944

AC XY:

7022

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0263

AC:

1094

AN:

41552

American (AMR)

AF:

0.0737

AC:

1127

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0848

AC:

294

AN:

3468

East Asian (EAS)

AF:

0.0234

AC:

121

AN:

5176

South Asian (SAS)

AF:

0.250

AC:

1207

AN:

4820

European-Finnish (FIN)

AF:

0.0985

AC:

1045

AN:

10612

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.134

AC:

9120

AN:

67978

Other (OTH)

AF:

0.0947

AC:

200

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

657

1314

1970

2627

3284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

360

540

720

900

<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:

0.110

Hom.:

786

TwinsUK

AF:

0.133

AC:

493

ALSPAC

AF:

0.132

AC:

510

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.124

AC:

1025

ExAC

AF:

0.106

AC:

12587

Asia WGS

AF:

0.130

AC:

452

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 05, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 04, 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

0.071

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.20

CADD

Benign

7.1

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.63

T;T;T;.

MetaRNN

Benign

0.0052

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.2

L;.;.;.

PhyloP100

0.43

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.90

N;.;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.25

T;.;T;T

Sift4G

Benign

0.081

T;.;T;T

Polyphen

0.0020

B;.;B;B

Vest4

0.043

ClinPred

0.0014

GERP RS

0.24

Varity_R

0.043

gMVP

0.21

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