rs1953087

Variant names:

• chr9-98461998-C-T
• rs1953087
• NM_005458.8:c.1000-7781G>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.1000-7781G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 152,086 control chromosomes in the GnomAD database, including 16,563 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 0.46 (16563 hom., cov: 33)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.292
• Publications: 1 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.1000-7781G>A		intron_variant	Intron 6 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.706-7781G>A		intron_variant	Intron 5 of 17		XP_016870820.1
GABBR2	XM_005252316.6	c.226-7781G>A		intron_variant	Intron 4 of 16		XP_005252373.1
GABBR2	XM_017015332.3	c.226-7781G>A		intron_variant	Intron 3 of 15		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.1000-7781G>A		intron_variant	Intron 6 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000634919.1	n.778-7781G>A		intron_variant	Intron 5 of 5	5
GABBR2	ENST00000637410.1	n.778-7781G>A		intron_variant	Intron 6 of 18	5

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69781 AN: 151968 Hom.: 16561 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.475

Gnomad ASJ AF: 0.630

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.483

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

GnomAD4 genome AF: 0.459 AC: 69799 AN: 152086 Hom.: 16563 Cov.: 33 AF XY: 0.455 AC XY: 33846 AN XY: 74350

African (AFR) AF: 0.372 AC: 15440 AN: 41484

American (AMR) AF: 0.474 AC: 7240 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 2185 AN: 3466

East Asian (EAS) AF: 0.240 AC: 1240 AN: 5172

South Asian (SAS) AF: 0.431 AC: 2082 AN: 4828

European-Finnish (FIN) AF: 0.472 AC: 4989 AN: 10580

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34947 AN: 67970

Other (OTH) AF: 0.478 AC: 1006 AN: 2106

Alfa AF: 0.485 Hom.: 2283

Bravo AF: 0.454

Asia WGS AF: 0.332 AC: 1156 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.2
DANN	Benign	0.53
PhyloP100		0.29
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: rs1953087; hg19: chr9-101224280;