9-98544339-C-T

Variant names:

• chr9-98544339-C-T
• rs2808523
• NM_005458.8:c.460-2296G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005458.8(GABBR2):​c.460-2296G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,970 control chromosomes in the GnomAD database, including 13,229 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.40 (13229 hom., cov: 31)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.679
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.460-2296G>A		intron_variant	Intron 2 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.166-2296G>A		intron_variant	Intron 1 of 17		XP_016870820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.460-2296G>A		intron_variant	Intron 2 of 18	1	NM_005458.8	ENSP00000259455.2

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61266 AN: 151852 Hom.: 13213 Cov.: 31

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.476

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.435

Gnomad OTH AF: 0.416

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.404 AC: 61324 AN: 151970 Hom.: 13229 Cov.: 31 AF XY: 0.414 AC XY: 30723 AN XY: 74272

African (AFR) AF: 0.250 AC: 10348 AN: 41446

American (AMR) AF: 0.477 AC: 7280 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1634 AN: 3468

East Asian (EAS) AF: 0.647 AC: 3334 AN: 5154

South Asian (SAS) AF: 0.393 AC: 1893 AN: 4816

European-Finnish (FIN) AF: 0.543 AC: 5737 AN: 10570

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.435 AC: 29556 AN: 67934

Other (OTH) AF: 0.416 AC: 877 AN: 2106

Alfa AF: 0.377 Hom.: 1712

Bravo AF: 0.396

Asia WGS AF: 0.485 AC: 1688 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.78
PhyloP100		0.68
Mutation Taster		=100/0	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: rs2808523; hg19: chr9-101306621;