rs58667649

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_StrongBS1BS2

The NM_021098.3(CACNA1H):c.5675G>A(p.Arg1892His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,552,680 control chromosomes in the GnomAD database, including 3 homozygotes. 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. R1892L) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00020 ( 3 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.683

Publications

8 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: Labcorp Genetics (formerly Invitae), G2P
epilepsy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=0.02485764).

BP6

Variant 16-1218439-G-A is Benign according to our data. Variant chr16-1218439-G-A is described in ClinVar as Benign. ClinVar VariationId is 1169274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000158 (24/152308) while in subpopulation SAS AF = 0.00145 (7/4824). AF 95% confidence interval is 0.00068. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.5675G>A	p.Arg1892His	missense	Exon 33 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.5657G>A	p.Arg1886His	missense	Exon 32 of 34	NP_001005407.1	O95180-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.5675G>A	p.Arg1892His	missense	Exon 33 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.5690G>A	p.Arg1897His	missense	Exon 32 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.5693G>A	p.Arg1898His	missense	Exon 32 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000341

AC:

AN:

158130

AF XY:

0.000393

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000804

Gnomad ASJ exome

AF:

0.000117

Gnomad EAS exome

AF:

0.000182

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.000198

AC:

277

AN:

1400372

Hom.:

Cov.:

AF XY:

0.000250

AC XY:

173

AN XY:

690952

show subpopulations

African (AFR)

AF:

0.0000631

AC:

AN:

31698

American (AMR)

AF:

0.0000557

AC:

AN:

35938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.0000837

AC:

AN:

35852

South Asian (SAS)

AF:

0.00174

AC:

138

AN:

79348

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47854

Middle Eastern (MID)

AF:

0.00265

AC:

AN:

5666

European-Non Finnish (NFE)

AF:

0.0000861

AC:

AN:

1080634

Other (OTH)

AF:

0.000412

AC:

AN:

58192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

104

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:

0.000158

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41556

American (AMR)

AF:

0.000261

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2114

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:

0.000102

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000196

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Idiopathic generalized epilepsy;C4310756:Hyperaldosteronism, familial, type IV (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.24

CADD

Benign

7.0

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.025

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

0.34

PhyloP100

-0.68

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.32

REVEL

Benign

0.29

Sift

Benign

0.12

Sift4G

Benign

0.11

Polyphen

0.70

Vest4

0.12

MVP

0.69

ClinPred

0.010

GERP RS

-0.61

Varity_R

0.053

gMVP

0.29

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over