rs199920661

chr16-1202218-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_021098.3(CACNA1H):c.1768C>T(p.Arg590Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,553,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R590Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CACNA1H
NM_021098.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.59

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18535319).

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1H	NM_021098.3 linkuse as main transcript	c.1768C>T	p.Arg590Trp	missense_variant	9/35	ENST00000348261.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1H	ENST00000348261.11 linkuse as main transcript	c.1768C>T	p.Arg590Trp	missense_variant	9/35	1	NM_021098.3	P4	O95180-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000964

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000534

AC:

AN:

149692

Hom.:

AF XY:

0.0000246

AC XY:

AN XY:

81212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000200

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000174

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1401286

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

AN XY:

691854

show subpopulations

Gnomad4 AFR exome

AF:

0.0000316

Gnomad4 AMR exome

AF:

0.000138

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000503

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000240

Gnomad4 OTH exome

AF:

0.0000860

GnomAD4 genome

AF:

0.0000459

AC:

AN:

152370

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000292

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000185

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign: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

Jul 21, 2021

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.1768C>T (p.R590W) alteration is located in exon 9 (coding exon 8) of the CACNA1H gene. This alteration results from a C to T substitution at nucleotide position 1768, causing the arginine (R) at amino acid position 590 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epilepsy, childhood absence, susceptibility to, 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 15, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

-0.070

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;.;.;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.87

D;D;D;.

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Uncertain

0.19

MutationAssessor

Uncertain

2.3

M;.;M;M

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.6

D;.;D;D

REVEL

Uncertain

0.35

Sift

Uncertain

0.012

D;.;D;D

Sift4G

Uncertain

0.015

D;.;D;D

Polyphen

0.95

P;.;D;D

Vest4

0.36

MVP

0.73

ClinPred

0.18

GERP RS

3.4

Varity_R

0.18

gMVP

0.57

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