9-98555639-C-T

Variant names:

• chr9-98555639-C-T
• rs2900512
• NM_005458.8:c.460-13596G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005458.8(GABBR2):​c.460-13596G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,028 control chromosomes in the GnomAD database, including 3,729 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 0.21 (3727 hom., cov: 32)
  • Exomes 𝑓: 0.31 (2 hom.)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.665
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 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.460-13596G>A		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.460-13596G>A		intron	N/A	ENSP00000259455.2
	GABBR2	ENST00000931526.1		c.460-13596G>A		intron	N/A	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.460-13596G>A		intron	N/A	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32406 AN: 151878 Hom.: 3722 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.313 AC: 10 AN: 32 Hom.: 2 Cov.: 0 AF XY: 0.250 AC XY: 7 AN XY: 28

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.286 AC: 8 AN: 28

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.213 AC: 32441 AN: 151996 Hom.: 3727 Cov.: 32 AF XY: 0.211 AC XY: 15656 AN XY: 74278

African (AFR) AF: 0.284 AC: 11743 AN: 41410

American (AMR) AF: 0.158 AC: 2409 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3462

East Asian (EAS) AF: 0.125 AC: 645 AN: 5168

South Asian (SAS) AF: 0.170 AC: 819 AN: 4814

European-Finnish (FIN) AF: 0.201 AC: 2129 AN: 10572

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13806 AN: 67972

Other (OTH) AF: 0.174 AC: 367 AN: 2112

Alfa AF: 0.199 Hom.: 7746

Bravo AF: 0.212

Asia WGS AF: 0.152 AC: 530 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.77
PhyloP100		0.67
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: rs2900512; hg19: chr9-101317921;