rs10985765

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_005458.8(GABBR2):c.2605A>G(p.Thr869Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,609,430 control chromosomes in the GnomAD database, including 31,221 homozygotes. 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.24 ( 4842 hom., cov: 33)

Exomes 𝑓: 0.19 ( 26379 hom. )

Consequence

GABBR2
NM_005458.8 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.15

Variant links:

Genes affected

GABBR2 (HGNC:4507): (gamma-aminobutyric acid type B receptor subunit 2) The multi-pass membrane protein encoded by this gene belongs to the G-protein coupled receptor 3 family and GABA-B receptor subfamily. The GABA-B receptors inhibit neuronal activity through G protein-coupled second-messenger systems, which regulate the release of neurotransmitters, and the activity of ion channels and adenylyl cyclase. This receptor subunit forms an active heterodimeric complex with GABA-B receptor subunit 1, neither of which is effective on its own. Allelic variants of this gene have been associated with nicotine dependence.[provided by RefSeq, Jan 2010]

GABBR2 links:

GABBR2 (HGNC:):

GABBR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABBR2. . Gene score misZ 4.6253 (greater than the threshold 3.09). Trascript score misZ 4.0975 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 59, neurodevelopmental disorder with poor language and loss of hand skills, atypical Rett syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038611293).

BP6

Variant 9-98293840-T-C is Benign according to our data. Variant chr9-98293840-T-C is described in ClinVar as [Benign]. Clinvar id is 1167954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABBR2	NM_005458.8 linkuse as main transcript	c.2605A>G	p.Thr869Ala	missense_variant	18/19	ENST00000259455.4	NP_005449.5	O75899H9NIL8
GABBR2	XM_017015331.3 linkuse as main transcript	c.2311A>G	p.Thr771Ala	missense_variant	17/18		XP_016870820.1
GABBR2	XM_005252316.6 linkuse as main transcript	c.1831A>G	p.Thr611Ala	missense_variant	16/17		XP_005252373.1
GABBR2	XM_017015332.3 linkuse as main transcript	c.1831A>G	p.Thr611Ala	missense_variant	15/16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4 linkuse as main transcript	c.2605A>G	p.Thr869Ala	missense_variant	18/19	1	NM_005458.8	ENSP00000259455.2		O75899
GABBR2	ENST00000637410.1 linkuse as main transcript	n.2383A>G		non_coding_transcript_exon_variant	18/19	5

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35858

AN:

152064

Hom.:

4839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.379

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.202

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.159

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.195

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.219

GnomAD3 exomes

AF:

0.191

AC:

47968

AN:

251242

Hom.:

5003

AF XY:

0.187

AC XY:

25351

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.385

Gnomad AMR exome

AF:

0.196

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.152

Gnomad SAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.177

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.186

AC:

271768

AN:

1457248

Hom.:

26379

Cov.:

AF XY:

0.186

AC XY:

135037

AN XY:

725200

show subpopulations

Gnomad4 AFR exome

AF:

0.376

Gnomad4 AMR exome

AF:

0.198

Gnomad4 ASJ exome

AF:

0.116

Gnomad4 EAS exome

AF:

0.181

Gnomad4 SAS exome

AF:

0.179

Gnomad4 FIN exome

AF:

0.193

Gnomad4 NFE exome

AF:

0.182

Gnomad4 OTH exome

AF:

0.189

GnomAD4 genome

AF:

0.236

AC:

35891

AN:

152182

Hom.:

4842

Cov.:

AF XY:

0.234

AC XY:

17410

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.379

Gnomad4 AMR

AF:

0.202

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.159

Gnomad4 SAS

AF:

0.170

Gnomad4 FIN

AF:

0.195

Gnomad4 NFE

AF:

0.181

Gnomad4 OTH

AF:

0.219

Alfa

AF:

0.187

Hom.:

5895

Bravo

AF:

0.244

TwinsUK

AF:

0.168

AC:

623

ALSPAC

AF:

0.188

AC:

723

ESP6500AA

AF:

0.383

AC:

1689

ESP6500EA

AF:

0.173

AC:

1485

ExAC

AF:

0.194

AC:

23532

Asia WGS

AF:

0.160

AC:

556

AN:

3478

EpiCase

AF:

0.174

EpiControl

AF:

0.178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

Epileptic encephalopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.074

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.43

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.60

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.52

REVEL

Benign

0.26

Sift

Benign

0.26

Sift4G

Benign

0.40

Polyphen

0.0

Vest4

0.026

MPC

0.88

ClinPred

0.0029

GERP RS

1.5

Varity_R

0.030

gMVP

0.11

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