rs369898856

Positions:

chr16-1202341-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000348261.11(CACNA1H):c.1891G>A(p.Gly631Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,571,956 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). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CACNA1H
ENST00000348261.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.248

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042584598).

BP6

Variant 16-1202341-G-A is Benign according to our data. Variant chr16-1202341-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 460056.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000129 (183/1419608) while in subpopulation MID AF= 0.00192 (11/5722). AF 95% confidence interval is 0.00108. There are 0 homozygotes in gnomad4_exome. There are 84 alleles in male gnomad4_exome subpopulation. Median coverage is 58. This position pass quality control queck.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.1891G>A	p.Gly631Arg	missense_variant	9/35	ENST00000348261.11	NP_066921.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.1891G>A	p.Gly631Arg	missense_variant	9/35	1	NM_021098.3	ENSP00000334198	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000121

AC:

AN:

174254

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

95192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000184

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.0000792

Gnomad SAS exome

AF:

0.0000421

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000136

Gnomad OTH exome

AF:

0.000631

GnomAD4 exome

AF:

0.000129

AC:

183

AN:

1419608

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

702494

show subpopulations

Gnomad4 AFR exome

AF:

0.0000615

Gnomad4 AMR exome

AF:

0.000232

Gnomad4 ASJ exome

AF:

0.0000788

Gnomad4 EAS exome

AF:

0.000108

Gnomad4 SAS exome

AF:

0.0000372

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000117

Gnomad4 OTH exome

AF:

0.000408

GnomAD4 genome

AF:

0.000125

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000201

Hom.:

Bravo

AF:

0.000117

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000125

AC:

ExAC

AF:

0.000104

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 19, 2022

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.25

CADD

Benign

2.3

DANN

Benign

0.61

DEOGEN2

Benign

0.15

T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.62

T;T;T;.

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.043

T;T;T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.32

N;.;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Benign

0.23

Sift

Benign

0.66

T;.;T;T

Sift4G

Benign

0.50

T;.;T;T

Polyphen

0.0090

B;.;B;B

Vest4

0.14

MutPred

0.26

Gain of MoRF binding (P = 0.0148);.;Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);

MVP

0.57

ClinPred

0.0067

GERP RS

-1.6

Varity_R

0.050

gMVP

0.38

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

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