rs2491397

Variant names:

• chr9-98442880-C-T
• rs2491397
• NM_005458.8:c.1236+11101G>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.1236+11101G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 152,104 control chromosomes in the GnomAD database, including 19,374 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 0.49 (19374 hom., cov: 32)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.258
• Publications: 9 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.1236+11101G>A		intron_variant	Intron 7 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.942+11101G>A		intron_variant	Intron 6 of 17		XP_016870820.1
GABBR2	XM_005252316.6	c.462+11101G>A		intron_variant	Intron 5 of 16		XP_005252373.1
GABBR2	XM_017015332.3	c.462+11101G>A		intron_variant	Intron 4 of 15		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.1236+11101G>A		intron_variant	Intron 7 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000637410.1	n.1014+11101G>A		intron_variant	Intron 7 of 18	5

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75239 AN: 151986 Hom.: 19378 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.459

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.512

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

GnomAD4 genome AF: 0.495 AC: 75255 AN: 152104 Hom.: 19374 Cov.: 32 AF XY: 0.488 AC XY: 36293 AN XY: 74332

African (AFR) AF: 0.452 AC: 18726 AN: 41458

American (AMR) AF: 0.458 AC: 7001 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2066 AN: 3470

East Asian (EAS) AF: 0.113 AC: 585 AN: 5178

South Asian (SAS) AF: 0.478 AC: 2302 AN: 4814

European-Finnish (FIN) AF: 0.483 AC: 5115 AN: 10586

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.553 AC: 37611 AN: 67998

Other (OTH) AF: 0.512 AC: 1081 AN: 2112

Alfa AF: 0.541 Hom.: 36928

Bravo AF: 0.485

Asia WGS AF: 0.299 AC: 1043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.1
DANN	Benign	0.60
PhyloP100		0.26
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: rs2491397; hg19: chr9-101205162;