rs10985765

chr9-98293840-T-Cchr9-98293840-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABBR2
• 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	UniProt
GABBR2	NM_005458.8	c.2605A>G	p.Thr869Ala	missense_variant	18/19	ENST00000259455.4
GABBR2	XM_017015331.3	c.2311A>G	p.Thr771Ala	missense_variant	17/18
GABBR2	XM_005252316.6	c.1831A>G	p.Thr611Ala	missense_variant	16/17
GABBR2	XM_017015332.3	c.1831A>G	p.Thr611Ala	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR2	ENST00000259455.4	c.2605A>G	p.Thr869Ala	missense_variant	18/19	1	NM_005458.8	P1
GABBR2	ENST00000637410.1	n.2383A>G		non_coding_transcript_exon_variant	18/19	5

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35858 AN: 152064 Hom.: 4839 Cov.: 33

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

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.: 29 AF XY: 0.186 AC XY: 135037 AN XY: 725200

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.: 33 AF XY: 0.234 AC XY: 17410 AN XY: 74412

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	14
Dann	Benign	0.96
DEOGEN2	Benign	0.074	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.26
Sift	Benign	0.26	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.026
MPC		0.88
ClinPred		0.0029	T
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

Other links and lift over

dbSNP: rs10985765; hg19: chr9-101056122; COSMIC: COSV52293539;