rs761199543

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 529579.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1H	NM_021098.3 link	c.3853G>A	p.Val1285Ile	missense_variant	Exon 19 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.3853G>A	p.Val1285Ile	missense_variant	Exon 19 of 35	1	NM_021098.3	ENSP00000334198.7	O95180-1
CACNA1H	ENST00000565831.6 link	c.3853G>A	p.Val1285Ile	missense_variant	Exon 18 of 33	1		ENSP00000455840.1	O95180-2
CACNA1H	ENST00000638323.1 link	c.3814G>A	p.Val1272Ile	missense_variant	Exon 19 of 35	5		ENSP00000492267.1	A0A1W2PR14
CACNA1H	ENST00000569107.5 link	c.76G>A	p.Val26Ile	missense_variant	Exon 2 of 17	1		ENSP00000454990.2	H3BNT0
CACNA1H	ENST00000564231.5 link	c.76G>A	p.Val26Ile	missense_variant	Exon 2 of 18	1		ENSP00000457555.2	H3BUA8
CACNA1H	ENST00000562079.5 link	c.76G>A	p.Val26Ile	missense_variant	Exon 2 of 17	1		ENSP00000454581.2	H3BMW6
CACNA1H	ENST00000637236.2 link	n.216G>A		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000492650.2	A0A1W2PS38
CACNA1H	ENST00000639478.1 link	n.3853G>A		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491945.1	A0A1W2PQW2
CACNA1H	ENST00000640028.1 link	n.*1766G>A		non_coding_transcript_exon_variant	Exon 19 of 35	5		ENSP00000491488.1	A0A1W2PQ19
CACNA1H	ENST00000640028.1 link	n.*1766G>A		3_prime_UTR_variant	Exon 19 of 35	5		ENSP00000491488.1	A0A1W2PQ19

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

GnomAD3 exomes

AF:

0.0000526

AC:

AN:

171184

Hom.:

AF XY:

0.0000324

AC XY:

AN XY:

92708

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000634

Gnomad4 AMR exome

AF:

0.000341

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000301

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000165

AC:

AN:

121314

Hom.:

Cov.:

AF XY:

0.0000178

AC XY:

AN XY:

56312

show subpopulations

Gnomad4 AFR

AF:

0.0000313

Gnomad4 AMR

AF:

0.000104

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000335

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:1

Nov 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Jun 20, 2022

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

0.079

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.30

CADD

Benign

6.3

DANN

Benign

0.95

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.70

T;T;T;.

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Uncertain

-0.037

MutationAssessor

Benign

1.2

L;.;L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.040

N;.;N;N

REVEL

Benign

0.11

Sift

Benign

0.42

T;.;T;T

Sift4G

Benign

0.58

T;.;T;T

Polyphen

0.0020

B;.;B;B

Vest4

0.12

MutPred

0.42

Gain of catalytic residue at V1285 (P = 0.0078);.;Gain of catalytic residue at V1285 (P = 0.0078);Gain of catalytic residue at V1285 (P = 0.0078);

MVP

0.50

ClinPred

0.054

GERP RS

1.7

Varity_R

0.025

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over