9-98685594-A-T

Variant names:

• chr9-98685594-A-T
• rs337526
• NM_005458.8:c.321+22823T>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.321+22823T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 152,198 control chromosomes in the GnomAD database, including 39,714 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 0.71 (39714 hom., cov: 34)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0690
• 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=-1.05).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.321+22823T>A		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.321+22823T>A		intron_variant	Intron 1 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000637717.1	c.-64+21650T>A		intron_variant	Intron 1 of 2	5		ENSP00000490789.1

Frequencies

GnomAD3 genomes AF: 0.713 AC: 108450 AN: 152080 Hom.: 39708 Cov.: 34

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.745

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

GnomAD4 genome AF: 0.713 AC: 108484 AN: 152198 Hom.: 39714 Cov.: 34 AF XY: 0.714 AC XY: 53130 AN XY: 74406

African (AFR) AF: 0.529 AC: 21974 AN: 41520

American (AMR) AF: 0.763 AC: 11676 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2875 AN: 3472

East Asian (EAS) AF: 0.779 AC: 4037 AN: 5180

South Asian (SAS) AF: 0.717 AC: 3456 AN: 4818

European-Finnish (FIN) AF: 0.776 AC: 8220 AN: 10596

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53641 AN: 67996

Other (OTH) AF: 0.745 AC: 1575 AN: 2114

Alfa AF: 0.670 Hom.: 2242

Bravo AF: 0.706

Asia WGS AF: 0.687 AC: 2390 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	3.1
DANN	Benign	0.33
PhyloP100		-0.069
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: rs337526; hg19: chr9-101447876;