rs747789914

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_021098.3(CACNA1H):c.5162G>A(p.Arg1721His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,609,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.71

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: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.947

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.5162G>A	p.Arg1721His	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.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.5177G>A	p.Arg1726His	missense_variant	Exon 28 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5180G>A	p.Arg1727His	missense_variant	Exon 28 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5144G>A	p.Arg1715His	missense_variant	Exon 28 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5177G>A	p.Arg1726His	missense_variant	Exon 29 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5123G>A	p.Arg1708His	missense_variant	Exon 29 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5144G>A	p.Arg1715His	missense_variant	Exon 28 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5105G>A	p.Arg1702His	missense_variant	Exon 28 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5144G>A	p.Arg1715His	missense_variant	Exon 28 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.5162G>A	p.Arg1721His	missense_variant	Exon 29 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.5162G>A		non_coding_transcript_exon_variant	Exon 29 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1114G>A		non_coding_transcript_exon_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*243G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3013G>A		non_coding_transcript_exon_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4606G>A		non_coding_transcript_exon_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.5144G>A		non_coding_transcript_exon_variant	Exon 28 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.5144G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*163G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.5162G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.5162G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5144G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.5162G>A		non_coding_transcript_exon_variant	Exon 29 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5162G>A		non_coding_transcript_exon_variant	Exon 29 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*163G>A		non_coding_transcript_exon_variant	Exon 28 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1114G>A		3_prime_UTR_variant	Exon 28 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*243G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3013G>A		3_prime_UTR_variant	Exon 29 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4606G>A		3_prime_UTR_variant	Exon 27 of 34			ENSP00000518758.1
CACNA1H	ENST00000711451.1 link	n.*163G>A		3_prime_UTR_variant	Exon 29 of 36			ENSP00000518763.1
CACNA1H	ENST00000711488.1 link	n.*163G>A		3_prime_UTR_variant	Exon 28 of 35			ENSP00000518777.1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151646

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000192

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000369

AC:

AN:

243956

AF XY:

0.0000376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.0000454

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1457994

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

725148

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33422

American (AMR)

AF:

0.0000449

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85916

European-Finnish (FIN)

AF:

0.000193

AC:

AN:

51882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000108

AC:

AN:

1110658

Other (OTH)

AF:

0.00

AC:

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000330

AC:

AN:

151646

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74110

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41378

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.000192

AC:

AN:

10428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67858

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000510

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV

Uncertain:1

Nov 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5162G>A (p.R1721H) alteration is located in exon 29 (coding exon 28) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 5162, causing the arginine (R) at amino acid position 1721 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Uncertain:1

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs747789914, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1H-related conditions. ClinVar contains an entry for this variant (Variation ID: 585648). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1721 of the CACNA1H protein (p.Arg1721His). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Mar 12, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.93

D;.;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.7

H;.;.;.

PhyloP100

9.7

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.0

D;.;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;D;D

Polyphen

1.0

D;.;D;D

Vest4

0.84

MVP

0.98

ClinPred

1.0

GERP RS

3.8

Varity_R

0.95

gMVP

0.94

Mutation Taster

=42/58

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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