rs368553931

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_021098.3(CACNA1H):c.6014G>A(p.Arg2005His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,546,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R2005C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0550

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09674695).

BP6

Variant 16-1219096-G-A is Benign according to our data. Variant chr16-1219096-G-A is described in ClinVar as Benign. ClinVar VariationId is 529567.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.6014G>A	p.Arg2005His	missense_variant	Exon 34 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.6014G>A	p.Arg2005His	missense_variant	Exon 34 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6 link	c.6029G>A	p.Arg2010His	missense_variant	Exon 33 of 34	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1 link	c.5999G>A	p.Arg2000His	missense_variant	Exon 33 of 34			ENSP00000518778.1
CACNA1H	ENST00000565831.7 link	c.5996G>A	p.Arg1999His	missense_variant	Exon 33 of 34	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000711450.1 link	c.5996G>A	p.Arg1999His	missense_variant	Exon 34 of 35			ENSP00000518762.1
CACNA1H	ENST00000564231.6 link	c.5981G>A	p.Arg1994His	missense_variant	Exon 34 of 35	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000638323.1 link	c.5975G>A	p.Arg1992His	missense_variant	Exon 34 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000562079.6 link	c.5963G>A	p.Arg1988His	missense_variant	Exon 33 of 34	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000711438.1 link	c.5957G>A	p.Arg1986His	missense_variant	Exon 33 of 34			ENSP00000518754.1
CACNA1H	ENST00000711482.1 link	c.6014G>A	p.Arg2005His	missense_variant	Exon 34 of 36			ENSP00000518771.1
CACNA1H	ENST00000711485.1 link	c.5963G>A	p.Arg1988His	missense_variant	Exon 33 of 35			ENSP00000518774.1
CACNA1H	ENST00000711455.1 link	c.5936G>A	p.Arg1979His	missense_variant	Exon 34 of 36			ENSP00000518768.1
CACNA1H	ENST00000711483.1 link	c.6014G>A	p.Arg2005His	missense_variant	Exon 34 of 35			ENSP00000518772.1
CACNA1H	ENST00000621827.2 link	n.6014G>A		non_coding_transcript_exon_variant	Exon 34 of 37	6		ENSP00000518766.1
CACNA1H	ENST00000637236.3 link	n.*1933G>A		non_coding_transcript_exon_variant	Exon 33 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1062G>A		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3832G>A		non_coding_transcript_exon_variant	Exon 34 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5458G>A		non_coding_transcript_exon_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*955G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*873G>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1593G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*681G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*648G>A		non_coding_transcript_exon_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711484.1 link	n.5963G>A		non_coding_transcript_exon_variant	Exon 33 of 35			ENSP00000518773.1
CACNA1H	ENST00000711486.1 link	n.6014G>A		non_coding_transcript_exon_variant	Exon 34 of 37			ENSP00000518775.1
CACNA1H	ENST00000711487.1 link	n.5981G>A		non_coding_transcript_exon_variant	Exon 34 of 36			ENSP00000518776.1
CACNA1H	ENST00000711488.1 link	n.*1130G>A		non_coding_transcript_exon_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000637236.3 link	n.*1933G>A		3_prime_UTR_variant	Exon 33 of 34	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.*1062G>A		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*3832G>A		3_prime_UTR_variant	Exon 34 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000711442.1 link	n.*5458G>A		3_prime_UTR_variant	Exon 32 of 34			ENSP00000518758.1
CACNA1H	ENST00000711448.1 link	n.*955G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518760.1
CACNA1H	ENST00000711449.1 link	n.*873G>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518761.1
CACNA1H	ENST00000711451.1 link	n.*1593G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518763.1
CACNA1H	ENST00000711452.1 link	n.*681G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518764.1
CACNA1H	ENST00000711453.1 link	n.*648G>A		3_prime_UTR_variant	Exon 35 of 36			ENSP00000518765.1
CACNA1H	ENST00000711488.1 link	n.*1130G>A		3_prime_UTR_variant	Exon 34 of 35			ENSP00000518777.1
CACNA1H	ENST00000711456.1 link	c.5887+445G>A		intron_variant	Intron 33 of 33			ENSP00000518769.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

149062

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000134

Gnomad AMR exome

AF:

0.0000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000947

AC:

132

AN:

1394540

Hom.:

Cov.:

AF XY:

0.0000931

AC XY:

AN XY:

687474

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31554

American (AMR)

AF:

0.0000563

AC:

AN:

35546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25060

East Asian (EAS)

AF:

0.0000281

AC:

AN:

35648

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5676

European-Non Finnish (NFE)

AF:

0.000114

AC:

123

AN:

1077092

Other (OTH)

AF:

0.0000519

AC:

AN:

57812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.0000460

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41436

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.0000776

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.000592

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000137

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Oct 22, 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

0.072

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.16

CADD

Benign

4.0

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.087

LIST_S2

Benign

0.68

T;T;T;.

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.097

T;T;T;T

MetaSVM

Uncertain

0.080

MutationAssessor

Benign

0.99

L;.;.;.

PhyloP100

0.055

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.26

Sift

Benign

0.095

T;.;T;T

Sift4G

Benign

0.22

T;.;T;T

Polyphen

0.0

B;.;B;B

Vest4

0.079

MVP

0.78

ClinPred

0.11

GERP RS

1.0

Varity_R

0.047

gMVP

0.27

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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