NM_021098.3:c.3853G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_021098.3(CACNA1H):c.3853G>A(p.Val1285Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 772,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. V1285D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000016 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.305

Publications

0 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0731816).

BP6

Variant 16-1210377-G-A is Benign according to our data. Variant chr16-1210377-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529579.

BS2

High AC in GnomAdExome4 at 25 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.3853G>A	p.Val1285Ile	missense	Exon 19 of 35	NP_066921.2	O95180-1
	CACNA1H	NM_001005407.2		c.3853G>A	p.Val1285Ile	missense	Exon 19 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.3853G>A	p.Val1285Ile	missense	Exon 19 of 35	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000569107.6	TSL:1	c.3853G>A	p.Val1285Ile	missense	Exon 19 of 34	ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000711493.1		c.3853G>A	p.Val1285Ile	missense	Exon 19 of 34	ENSP00000518778.1	A0AAA9YHG8

Frequencies

GnomAD3 genomes

AF:

0.0000165

AC:

AN:

121314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000104

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000526

AC:

AN:

171184

AF XY:

0.0000324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000261

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.0000384

AC:

AN:

650874

Hom.:

Cov.:

AF XY:

0.0000363

AC XY:

AN XY:

330296

show subpopulations

African (AFR)

AF:

0.0000634

AC:

AN:

15776

American (AMR)

AF:

0.000341

AC:

AN:

29318

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12956

East Asian (EAS)

AF:

0.00

AC:

AN:

11596

South Asian (SAS)

AF:

0.00

AC:

AN:

66880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

20274

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3468

European-Non Finnish (NFE)

AF:

0.0000301

AC:

AN:

465270

Other (OTH)

AF:

0.00

AC:

AN:

25336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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:

0.0000165

AC:

AN:

121314

Hom.:

Cov.:

AF XY:

0.0000178

AC XY:

AN XY:

56312

show subpopulations

African (AFR)

AF:

0.0000313

AC:

AN:

31924

American (AMR)

AF:

0.000104

AC:

AN:

9594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3234

East Asian (EAS)

AF:

0.00

AC:

AN:

3490

South Asian (SAS)

AF:

0.00

AC:

AN:

3408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61560

Other (OTH)

AF:

0.00

AC:

AN:

1674

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000335

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epilepsy, childhood absence, susceptibility to, 6;C4310756:Hyperaldosteronism, familial, type IV (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.30

CADD

Benign

6.3

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.70

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.073

MetaSVM

Uncertain

-0.037

MutationAssessor

Benign

1.2

PhyloP100

-0.30

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.040

REVEL

Benign

0.11

Sift

Benign

0.42

Sift4G

Benign

0.58

Polyphen

0.0020

Vest4

0.12

MutPred

0.42

Gain of catalytic residue at V1285 (P = 0.0078)

MVP

0.50

ClinPred

0.054

GERP RS

1.7

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.025

gMVP

0.43

Mutation Taster

=93/7

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over