rs200158741

Variant names:

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.6943G>A(p.Gly2315Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,612,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.88

Publications

3 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=0.054529876).

BP6

Variant 16-1220875-G-A is Benign according to our data. Variant chr16-1220875-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 460182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000283 (43/152092) while in subpopulation EAS AF = 0.00135 (7/5170). AF 95% confidence interval is 0.000635. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 43 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1H	NM_021098.3	MANE Select	c.6943G>A	p.Gly2315Ser	missense	Exon 35 of 35	NP_066921.2
	CACNA1H	NM_001005407.2		c.6925G>A	p.Gly2309Ser	missense	Exon 34 of 34	NP_001005407.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1H	ENST00000348261.11	TSL:1 MANE Select	c.6943G>A	p.Gly2315Ser	missense	Exon 35 of 35	ENSP00000334198.7
CACNA1H	ENST00000569107.6	TSL:1	c.6958G>A	p.Gly2320Ser	missense	Exon 34 of 34	ENSP00000454990.2
CACNA1H	ENST00000711493.1		c.6928G>A	p.Gly2310Ser	missense	Exon 34 of 34	ENSP00000518778.1

Frequencies

GnomAD3 genomes

AF:

0.000283

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000499

AC:

124

AN:

248284

AF XY:

0.000481

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.00156

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000463

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000318

AC:

464

AN:

1460422

Hom.:

Cov.:

AF XY:

0.000299

AC XY:

217

AN XY:

726502

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000358

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26130

East Asian (EAS)

AF:

0.00118

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52238

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000282

AC:

314

AN:

1111784

Other (OTH)

AF:

0.000447

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

111

139

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000283

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41418

American (AMR)

AF:

0.000196

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67992

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

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:

0.000396

Hom.:

Bravo

AF:

0.000344

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000612

AC:

ExAC

AF:

0.000505

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.00101

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.27

CADD

Benign

0.092

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.10

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.055

MetaSVM

Uncertain

-0.091

MutationAssessor

Benign

0.34

PhyloP100

-1.9

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.39

REVEL

Uncertain

0.32

Sift

Benign

0.46

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.045

MVP

0.72

ClinPred

0.0024

GERP RS

-3.5

Varity_R

0.075

gMVP

0.085

Mutation Taster

=99/1

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over