9-98322519-G-C

Variant names:

• chr9-98322519-G-C
• rs998952
• NM_005458.8:c.1894-11314C>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.1894-11314C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 151,472 control chromosomes in the GnomAD database, including 3,511 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 0.19 (3511 hom., cov: 29)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.718
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.1894-11314C>G		intron_variant	Intron 13 of 18	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1600-11314C>G		intron_variant	Intron 12 of 17		XP_016870820.1
GABBR2	XM_005252316.6	c.1120-11314C>G		intron_variant	Intron 11 of 16		XP_005252373.1
GABBR2	XM_017015332.3	c.1120-11314C>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.1894-11314C>G		intron_variant	Intron 13 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000634457.1	c.232-16174C>G		intron_variant	Intron 2 of 3	5		ENSP00000489352.1
GABBR2	ENST00000635462.1	n.389-11314C>G		intron_variant	Intron 3 of 4	2
GABBR2	ENST00000637410.1	n.1672-11314C>G		intron_variant	Intron 13 of 18	5

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29136 AN: 151354 Hom.: 3512 Cov.: 29

Gnomad AFR AF: 0.0479

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.278

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.249

Gnomad OTH AF: 0.212

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

GnomAD4 genome AF: 0.192 AC: 29136 AN: 151472 Hom.: 3511 Cov.: 29 AF XY: 0.196 AC XY: 14522 AN XY: 73952

African (AFR) AF: 0.0478 AC: 1976 AN: 41332

American (AMR) AF: 0.216 AC: 3279 AN: 15208

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3466

East Asian (EAS) AF: 0.275 AC: 1400 AN: 5094

South Asian (SAS) AF: 0.277 AC: 1324 AN: 4788

European-Finnish (FIN) AF: 0.258 AC: 2688 AN: 10424

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.249 AC: 16903 AN: 67854

Other (OTH) AF: 0.214 AC: 450 AN: 2100

Alfa AF: 0.222 Hom.: 539

Bravo AF: 0.182

Asia WGS AF: 0.256 AC: 892 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.8
DANN	Benign	0.50
PhyloP100		0.72
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: rs998952; hg19: chr9-101084801;