chr9-98293840-T-C

Variant names:

• chr9-98293840-T-C
• rs10985765
• NM_005458.8:c.2605A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 1.15
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 59

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with poor language and loss of hand skills

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005458.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.2605A>G	p.Thr869Ala	missense	Exon 18 of 19	NP_005449.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.2605A>G	p.Thr869Ala	missense	Exon 18 of 19	ENSP00000259455.2
	GABBR2	ENST00000637410.1	TSL:5	n.2383A>G		non_coding_transcript_exon	Exon 18 of 19

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

GnomAD2 exomes AF: 0.191 AC: 47968 AN: 251242 AF XY: 0.187

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 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

African (AFR) AF: 0.376 AC: 12420 AN: 33046

American (AMR) AF: 0.198 AC: 8868 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3018 AN: 26108

East Asian (EAS) AF: 0.181 AC: 7197 AN: 39672

South Asian (SAS) AF: 0.179 AC: 15390 AN: 86132

European-Finnish (FIN) AF: 0.193 AC: 10324 AN: 53390

Middle Eastern (MID) AF: 0.203 AC: 1168 AN: 5758

European-Non Finnish (NFE) AF: 0.182 AC: 201993 AN: 1108232

Other (OTH) AF: 0.189 AC: 11390 AN: 60226

GnomAD4 genome AF: 0.236 AC: 35891 AN: 152182 Hom.: 4842 Cov.: 33 AF XY: 0.234 AC XY: 17410 AN XY: 74412

African (AFR) AF: 0.379 AC: 15732 AN: 41494

American (AMR) AF: 0.202 AC: 3091 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3470

East Asian (EAS) AF: 0.159 AC: 827 AN: 5188

South Asian (SAS) AF: 0.170 AC: 823 AN: 4828

European-Finnish (FIN) AF: 0.195 AC: 2060 AN: 10590

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12275 AN: 68004

Other (OTH) AF: 0.219 AC: 462 AN: 2108

Alfa AF: 0.196 Hom.: 8550

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

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

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