rs370079169

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021098.3(CACNA1H):c.4790G>A(p.Arg1597Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,563,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1597W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.18

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013262987).

BP6

Variant 16-1213792-G-A is Benign according to our data. Variant chr16-1213792-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529681.

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 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.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.4805G>A	p.Arg1602Gln	missense_variant	Exon 26 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.4808G>A	p.Arg1603Gln	missense_variant	Exon 26 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.4772G>A	p.Arg1591Gln	missense_variant	Exon 26 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.4805G>A	p.Arg1602Gln	missense_variant	Exon 27 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.4751G>A	p.Arg1584Gln	missense_variant	Exon 27 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.4772G>A	p.Arg1591Gln	missense_variant	Exon 26 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.4733G>A	p.Arg1578Gln	missense_variant	Exon 26 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.4772G>A	p.Arg1591Gln	missense_variant	Exon 26 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 of 35			ENSP00000518772.1
CACNA1H	ENST00000711456.1 link	c.4790G>A	p.Arg1597Gln	missense_variant	Exon 27 of 34			ENSP00000518769.1
CACNA1H	ENST00000621827.2 link	n.4790G>A		non_coding_transcript_exon_variant	Exon 27 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*742G>A		non_coding_transcript_exon_variant	Exon 26 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.4728G>A		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*2641G>A		non_coding_transcript_exon_variant	Exon 27 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4234G>A		non_coding_transcript_exon_variant	Exon 25 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.4772G>A		non_coding_transcript_exon_variant	Exon 26 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.4772G>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.4867G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.4790G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.4790G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.4772G>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.4790G>A		non_coding_transcript_exon_variant	Exon 27 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.4790G>A		non_coding_transcript_exon_variant	Exon 27 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.4849G>A		non_coding_transcript_exon_variant	Exon 26 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*742G>A		3_prime_UTR_variant	Exon 26 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000640028.1 link	n.*2641G>A		3_prime_UTR_variant	Exon 27 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*4234G>A		3_prime_UTR_variant	Exon 25 of 34			ENSP00000518758.1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000369

AC:

AN:

173394

AF XY:

0.000417

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00556

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000206

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

237

AN:

1411470

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

127

AN XY:

698010

show subpopulations

African (AFR)

AF:

0.000154

AC:

AN:

32370

American (AMR)

AF:

0.0000539

AC:

AN:

37114

Ashkenazi Jewish (ASJ)

AF:

0.00473

AC:

120

AN:

25366

East Asian (EAS)

AF:

0.00

AC:

AN:

37066

South Asian (SAS)

AF:

0.0000248

AC:

AN:

80776

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.0000753

AC:

AN:

1088816

Other (OTH)

AF:

0.000443

AC:

AN:

58736

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.000263

AC:

AN:

151984

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.0000725

AC:

AN:

41402

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00721

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000557

Hom.:

Bravo

AF:

0.000261

ESP6500AA

AF:

0.000254

AC:

ESP6500EA

AF:

0.000365

AC:

ExAC

AF:

0.000280

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.4790G>A (p.R1597Q) alteration is located in exon 27 (coding exon 26) of the CACNA1H gene. This alteration results from a G to A substitution at nucleotide position 4790, causing the arginine (R) at amino acid position 1597 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CACNA1H-related disorder

Benign:1

Apr 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Benign:1

Apr 03, 2024

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

0.16

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

T;.;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.69

LIST_S2

Uncertain

0.95

D;D;D;.

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.62

PhyloP100

1.2

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.20

T;.;T;T

Sift4G

Benign

0.26

T;.;T;T

Polyphen

0.99

D;.;D;D

Vest4

0.62

MVP

0.89

ClinPred

0.16

GERP RS

3.9

Varity_R

0.19

gMVP

0.59

Mutation Taster

=80/20

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

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