NM_005458.8:c.732+5469A>G

Variant names:

• chr9-98490944-T-C
• rs2779551
• NM_005458.8:c.732+5469A>G

Variant summary

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

The NM_005458.8(GABBR2):​c.732+5469A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0699 in 151,770 control chromosomes in the GnomAD database, including 460 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 0.070 (460 hom., cov: 32)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.262
• 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)
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.732+5469A>G		intron	N/A	NP_005449.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.732+5469A>G		intron	N/A	ENSP00000259455.2
	GABBR2	ENST00000477471.1	TSL:3	n.519+5469A>G		intron	N/A
	GABBR2	ENST00000634227.1	TSL:5	n.506+5469A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 10612 AN: 151700 Hom.: 461 Cov.: 32

Gnomad AFR AF: 0.0838

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0450

Gnomad OTH AF: 0.0801

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

GnomAD4 genome AF: 0.0699 AC: 10616 AN: 151770 Hom.: 460 Cov.: 32 AF XY: 0.0725 AC XY: 5373 AN XY: 74130

African (AFR) AF: 0.0839 AC: 3468 AN: 41352

American (AMR) AF: 0.108 AC: 1646 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3472

East Asian (EAS) AF: 0.168 AC: 870 AN: 5170

South Asian (SAS) AF: 0.0518 AC: 248 AN: 4790

European-Finnish (FIN) AF: 0.0639 AC: 667 AN: 10440

Middle Eastern (MID) AF: 0.0458 AC: 13 AN: 284

European-Non Finnish (NFE) AF: 0.0450 AC: 3061 AN: 67982

Other (OTH) AF: 0.0786 AC: 165 AN: 2100

Alfa AF: 0.0619 Hom.: 517

Bravo AF: 0.0783

Asia WGS AF: 0.117 AC: 407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.6
DANN	Benign	0.62
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2779551; hg19: chr9-101253226;