rs1999501

Variant names:

• chr9-98590697-G-A
• rs1999501
• NM_005458.8:c.322-12625C>T

Variant summary

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

The NM_005458.8(GABBR2):​c.322-12625C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0789 in 152,228 control chromosomes in the GnomAD database, including 1,042 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 0.079 (1042 hom., cov: 32)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.344
• Publications: 3 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.322-12625C>T		intron_variant	Intron 1 of 18	ENST00000259455.4	NP_005449.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.322-12625C>T		intron_variant	Intron 1 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000637717.1	c.-63-12625C>T		intron_variant	Intron 1 of 2	5		ENSP00000490789.1
GABBR2	ENST00000634227.1	n.96-12625C>T		intron_variant	Intron 1 of 5	5

Frequencies

GnomAD3 genomes AF: 0.0789 AC: 11996 AN: 152110 Hom.: 1041 Cov.: 32

Gnomad AFR AF: 0.0608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.0871

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0496

Gnomad OTH AF: 0.0747

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

GnomAD4 genome AF: 0.0789 AC: 12016 AN: 152228 Hom.: 1042 Cov.: 32 AF XY: 0.0826 AC XY: 6144 AN XY: 74420

African (AFR) AF: 0.0609 AC: 2527 AN: 41528

American (AMR) AF: 0.173 AC: 2641 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3472

East Asian (EAS) AF: 0.464 AC: 2391 AN: 5158

South Asian (SAS) AF: 0.0865 AC: 418 AN: 4830

European-Finnish (FIN) AF: 0.0369 AC: 392 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0496 AC: 3374 AN: 68020

Other (OTH) AF: 0.0768 AC: 162 AN: 2110

Alfa AF: 0.0577 Hom.: 51

Bravo AF: 0.0895

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.86
PhyloP100		-0.34
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: rs1999501; hg19: chr9-101352979;