chr9-98523132-C-A

Variant names:

• chr9-98523132-C-A
• rs2779577
• NM_005458.8:c.630+18741G>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.630+18741G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 152,308 control chromosomes in the GnomAD database, including 70,686 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 0.96 (70686 hom., cov: 33)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0930
• 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.981 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.630+18741G>T		intron_variant	Intron 3 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.336+18741G>T		intron_variant	Intron 2 of 17		XP_016870820.1
GABBR2	XM_005252316.6	c.-145+15414G>T		intron_variant	Intron 1 of 16		XP_005252373.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.630+18741G>T		intron_variant	Intron 3 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000477471.1	n.417+18741G>T		intron_variant	Intron 2 of 4	3
GABBR2	ENST00000634227.1	n.404+18741G>T		intron_variant	Intron 3 of 5	5
GABBR2	ENST00000637410.1	n.408+18741G>T		intron_variant	Intron 3 of 18	5

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146571 AN: 152190 Hom.: 70633 Cov.: 33

Gnomad AFR AF: 0.989

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.905

Gnomad ASJ AF: 0.991

Gnomad EAS AF: 0.936

Gnomad SAS AF: 0.947

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.975

Gnomad NFE AF: 0.961

Gnomad OTH AF: 0.957

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

GnomAD4 genome AF: 0.963 AC: 146682 AN: 152308 Hom.: 70686 Cov.: 33 AF XY: 0.962 AC XY: 71652 AN XY: 74472

African (AFR) AF: 0.989 AC: 41112 AN: 41564

American (AMR) AF: 0.904 AC: 13836 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.991 AC: 3440 AN: 3472

East Asian (EAS) AF: 0.936 AC: 4854 AN: 5188

South Asian (SAS) AF: 0.948 AC: 4564 AN: 4814

European-Finnish (FIN) AF: 0.969 AC: 10280 AN: 10614

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.961 AC: 65382 AN: 68036

Other (OTH) AF: 0.955 AC: 2018 AN: 2114

Alfa AF: 0.962 Hom.: 8748

Bravo AF: 0.959

Asia WGS AF: 0.937 AC: 3250 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.2
DANN	Benign	0.25
PhyloP100		0.093
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: rs2779577; hg19: chr9-101285414;