9-98707652-C-G

Variant names:

• chr9-98707652-C-G
• rs509747
• NM_005458.8:c.321+765G>C

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+765G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,202 control chromosomes in the GnomAD database, including 38,981 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 0.70 (38981 hom., cov: 34)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284
• Publications: 4 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)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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=-0.7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005458.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.321+765G>C		intron	N/A	NP_005449.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.321+765G>C		intron	N/A	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.321+765G>C		intron	N/A	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.321+765G>C		intron	N/A	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106979 AN: 152082 Hom.: 38982 Cov.: 34

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.773

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.739

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

GnomAD4 genome AF: 0.703 AC: 106994 AN: 152202 Hom.: 38981 Cov.: 34 AF XY: 0.704 AC XY: 52369 AN XY: 74402

African (AFR) AF: 0.490 AC: 20318 AN: 41504

American (AMR) AF: 0.760 AC: 11637 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2905 AN: 3472

East Asian (EAS) AF: 0.820 AC: 4239 AN: 5168

South Asian (SAS) AF: 0.720 AC: 3473 AN: 4826

European-Finnish (FIN) AF: 0.773 AC: 8202 AN: 10606

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53630 AN: 68002

Other (OTH) AF: 0.739 AC: 1563 AN: 2116

Alfa AF: 0.728 Hom.: 4886

Bravo AF: 0.695

Asia WGS AF: 0.707 AC: 2460 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.51
PhyloP100		0.28
PromoterAI		-0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs509747; hg19: chr9-101469934; COSMIC: COSV52320867; COSMIC: COSV52320867;