rs121913125

Positions:

chr15-26580351-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_000814.6(GABRB3):c.650G>A(p.Arg217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GABRB3
NM_000814.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.71

Variant links:

Genes affected

GABRB3 (HGNC:4083): (gamma-aminobutyric acid type A receptor subunit beta3) This gene encodes a member of the ligand-gated ionic channel family. The encoded protein is one the subunits of a multi-subunit chloride channel that serves as the receptor for gamma-aminobutyric acid, a major inhibitory neurotransmitter of the mammalian nervous system. This gene is located on the long arm of chromosome 15 in a cluster with two other genes encoding related subunits of the family. This gene may be associated with the pathogenesis of several disorders including Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Jul 2013]

GABRB3 links:

GABRB3 (HGNC:):

GABRB3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABRB3. . Gene score misZ 3.3856 (greater than the threshold 3.09). Trascript score misZ 4.4544 (greater than threshold 3.09). GenCC has associacion of gene with childhood absence epilepsy, developmental and epileptic encephalopathy, 43, developmental and epileptic encephalopathy, Lennox-Gastaut syndrome, epilepsy, childhood absence, susceptibility to, 5.

BP4

Computational evidence support a benign effect (MetaRNN=0.123971224).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRB3	NM_000814.6 linkuse as main transcript	c.650G>A	p.Arg217His	missense_variant	6/9	ENST00000311550.10	NP_000805.1	P28472-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRB3	ENST00000311550.10 linkuse as main transcript	c.650G>A	p.Arg217His	missense_variant	6/9	1	NM_000814.6	ENSP00000308725.5		P28472-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251428

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Developmental and epileptic encephalopathy, 43

Uncertain:2

Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 10, 2020	- -

SUDDEN INFANT DEATH SYNDROME

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Robert's Program, Boston Children's Hospital

Oct 01, 2021

We classify this variant as a variant of uncertain significance using ACMG/AMP criteria. As this variant has functional evidence supporting pathogenicty, we suspect this variant is favoring pathogenic. -

Insomnia

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2002

- -

Epilepsy, childhood absence, susceptibility to, 1;C2677087:Epilepsy, childhood absence, susceptibility to, 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Benign

0.94

DEOGEN2

Benign

0.35

.;T;.;.;.;.;.;.;.

Eigen

Benign

-0.050

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.93

.;D;D;D;D;.;D;D;.

M_CAP

Benign

0.033

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.4

.;L;.;.;L;.;.;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

.;N;.;N;N;.;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.38

.;T;.;T;T;.;.;T;T

Sift4G

Benign

0.66

T;T;T;T;T;.;.;T;T

Polyphen

0.036, 0.22, 0.029

.;B;.;B;B;.;.;.;.

Vest4

0.48

MVP

0.65

MPC

2.4

ClinPred

0.12

GERP RS

5.3

Varity_R

0.20

gMVP

0.61

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