rs1054645

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.6230G>A(p.Arg2077His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,523,120 control chromosomes in the GnomAD database, including 285,545 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R2077C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.65 ( 32651 hom., cov: 35)

Exomes 𝑓: 0.60 ( 252894 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.784

Publications

49 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=8.9449054E-7).

BP6

Variant 16-1220162-G-A is Benign according to our data. Variant chr16-1220162-G-A is described in ClinVar as Benign. ClinVar VariationId is 96016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6230G>A	p.Arg2077His	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.6230G>A	p.Arg2077His	missense_variant	Exon 35 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.6245G>A	p.Arg2082His	missense_variant	Exon 34 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.6215G>A	p.Arg2072His	missense_variant	Exon 34 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.6212G>A	p.Arg2071His	missense_variant	Exon 34 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.6212G>A	p.Arg2071His	missense_variant	Exon 35 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.6197G>A	p.Arg2066His	missense_variant	Exon 35 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.6191G>A	p.Arg2064His	missense_variant	Exon 35 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.6179G>A	p.Arg2060His	missense_variant	Exon 34 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.6173G>A	p.Arg2058His	missense_variant	Exon 34 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.6123G>A	p.Ala2041Ala	splice_region_variant, synonymous_variant	Exon 36 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.6072G>A	p.Ala2024Ala	splice_region_variant, synonymous_variant	Exon 35 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.6045G>A	p.Ala2015Ala	splice_region_variant, synonymous_variant	Exon 36 of 36			ENSP00000518768.1
CACNA1H	ENST00000637236.3 link	n.*2149G>A		non_coding_transcript_exon_variant	Exon 34 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1278G>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*4048G>A		non_coding_transcript_exon_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5674G>A		non_coding_transcript_exon_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1171G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1089G>A		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1809G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*897G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*864G>A		non_coding_transcript_exon_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*144G>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6230G>A		non_coding_transcript_exon_variant	Exon 35 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.6197G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1346G>A		non_coding_transcript_exon_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000711483.1 link	c.*144G>A		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.*144G>A		3_prime_UTR_variant	Exon 34 of 34			ENSP00000518769.1
CACNA1H	ENST00000637236.3 link	n.*2149G>A		3_prime_UTR_variant	Exon 34 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1278G>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*4048G>A		3_prime_UTR_variant	Exon 35 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5674G>A		3_prime_UTR_variant	Exon 33 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*1171G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*1089G>A		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1809G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*897G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*864G>A		3_prime_UTR_variant	Exon 36 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.*144G>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518773.1
CACNA1H	ENST00000711488.1 link	n.*1346G>A		3_prime_UTR_variant	Exon 35 of 35			ENSP00000518777.1
CACNA1H	ENST00000621827.2 link	n.6121+109G>A		intron_variant	Intron 35 of 36	6		ENSP00000518766.1

Frequencies

GnomAD3 genomes

AF:

0.650

AC:

98790

AN:

152052

Hom.:

32623

Cov.:

show subpopulations

Gnomad AFR

AF:

0.700

Gnomad AMI

AF:

0.573

Gnomad AMR

AF:

0.702

Gnomad ASJ

AF:

0.711

Gnomad EAS

AF:

0.876

Gnomad SAS

AF:

0.559

Gnomad FIN

AF:

0.710

Gnomad MID

AF:

0.709

Gnomad NFE

AF:

0.585

Gnomad OTH

AF:

0.655

GnomAD2 exomes

AF:

0.657

AC:

109910

AN:

167372

AF XY:

0.646

show subpopulations

Gnomad AFR exome

AF:

0.705

Gnomad AMR exome

AF:

0.747

Gnomad ASJ exome

AF:

0.709

Gnomad EAS exome

AF:

0.895

Gnomad FIN exome

AF:

0.701

Gnomad NFE exome

AF:

0.595

Gnomad OTH exome

AF:

0.646

GnomAD4 exome

AF:

0.604

AC:

827558

AN:

1370950

Hom.:

252894

Cov.:

AF XY:

0.602

AC XY:

405972

AN XY:

674462

show subpopulations

African (AFR)

AF:

0.709

AC:

20105

AN:

28372

American (AMR)

AF:

0.735

AC:

24437

AN:

33246

Ashkenazi Jewish (ASJ)

AF:

0.697

AC:

14833

AN:

21278

East Asian (EAS)

AF:

0.901

AC:

32252

AN:

35778

South Asian (SAS)

AF:

0.561

AC:

40542

AN:

72308

European-Finnish (FIN)

AF:

0.690

AC:

33565

AN:

48680

Middle Eastern (MID)

AF:

0.702

AC:

3785

AN:

5390

European-Non Finnish (NFE)

AF:

0.582

AC:

622803

AN:

1069526

Other (OTH)

AF:

0.625

AC:

35236

AN:

56372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

19727

39454

59182

78909

98636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17760

35520

53280

71040

88800

<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:

0.650

AC:

98862

AN:

152170

Hom.:

32651

Cov.:

AF XY:

0.657

AC XY:

48845

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.699

AC:

29030

AN:

41522

American (AMR)

AF:

0.703

AC:

10758

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.711

AC:

2469

AN:

3472

East Asian (EAS)

AF:

0.876

AC:

4513

AN:

5152

South Asian (SAS)

AF:

0.559

AC:

2692

AN:

4820

European-Finnish (FIN)

AF:

0.710

AC:

7535

AN:

10610

Middle Eastern (MID)

AF:

0.701

AC:

206

AN:

294

European-Non Finnish (NFE)

AF:

0.585

AC:

39742

AN:

67968

Other (OTH)

AF:

0.660

AC:

1396

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1845

3690

5534

7379

9224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.612

Hom.:

76473

Bravo

AF:

0.659

TwinsUK

AF:

0.570

AC:

2113

ALSPAC

AF:

0.589

AC:

2269

ESP6500AA

AF:

0.728

AC:

2894

ESP6500EA

AF:

0.608

AC:

5031

ExAC

AF:

0.627

AC:

73990

Asia WGS

AF:

0.720

AC:

2501

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

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 27, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Epilepsy, childhood absence, susceptibility to, 6

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 03, 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

0.065

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.74

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.086

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.60

T;T;T;.

MetaRNN

Benign

8.9e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

N;.;.;.

PhyloP100

-0.78

PrimateAI

Benign

0.41

PROVEAN

Benign

0.45

N;.;N;N

REVEL

Benign

0.033

Sift

Benign

0.59

T;.;T;T

Sift4G

Benign

0.59

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.033

ClinPred

0.0018

GERP RS

0.76

Varity_R

0.022

gMVP

0.20

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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