chr9-98312590-T-C

Variant names:

• chr9-98312590-T-C
• rs13286336
• NM_005458.8:c.1894-1385A>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.1894-1385A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 152,122 control chromosomes in the GnomAD database, including 5,141 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 0.25 (5141 hom., cov: 32)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.160
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.1894-1385A>G		intron_variant	Intron 13 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1600-1385A>G		intron_variant	Intron 12 of 17		XP_016870820.1
GABBR2	XM_005252316.6	c.1120-1385A>G		intron_variant	Intron 11 of 16		XP_005252373.1
GABBR2	XM_017015332.3	c.1120-1385A>G		intron_variant	Intron 10 of 15		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.1894-1385A>G		intron_variant	Intron 13 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000634457.1	c.232-6245A>G		intron_variant	Intron 2 of 3	5		ENSP00000489352.1
GABBR2	ENST00000635462.1	n.389-1385A>G		intron_variant	Intron 3 of 4	2
GABBR2	ENST00000637410.1	n.1672-1385A>G		intron_variant	Intron 13 of 18	5

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38405 AN: 152004 Hom.: 5148 Cov.: 32

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.284

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

GnomAD4 genome AF: 0.252 AC: 38404 AN: 152122 Hom.: 5141 Cov.: 32 AF XY: 0.254 AC XY: 18876 AN XY: 74374

African (AFR) AF: 0.261 AC: 10821 AN: 41476

American (AMR) AF: 0.278 AC: 4252 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1114 AN: 3472

East Asian (EAS) AF: 0.368 AC: 1903 AN: 5176

South Asian (SAS) AF: 0.402 AC: 1934 AN: 4812

European-Finnish (FIN) AF: 0.176 AC: 1864 AN: 10594

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15601 AN: 67984

Other (OTH) AF: 0.281 AC: 595 AN: 2116

Alfa AF: 0.229 Hom.: 522

Bravo AF: 0.260

Asia WGS AF: 0.349 AC: 1212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.4
DANN	Benign	0.45
PhyloP100		-0.16
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: rs13286336; hg19: chr9-101074872;