chr9-98672993-G-C

Variant names:

• chr9-98672993-G-C
• rs10512258
• NM_005458.8:c.321+35424C>G

Variant summary

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

The NM_005458.8(GABBR2):​c.321+35424C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 152,082 control chromosomes in the GnomAD database, including 39,231 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 0.71 (39231 hom., cov: 33)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.727
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.825 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.321+35424C>G		intron_variant	Intron 1 of 18	ENST00000259455.4	NP_005449.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.321+35424C>G		intron_variant	Intron 1 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000637717.1	c.-64+34251C>G		intron_variant	Intron 1 of 2	5		ENSP00000490789.1

Frequencies

GnomAD3 genomes AF: 0.710 AC: 107821 AN: 151964 Hom.: 39228 Cov.: 33

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.856

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.847

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.774

Gnomad OTH AF: 0.746

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

GnomAD4 genome AF: 0.709 AC: 107854 AN: 152082 Hom.: 39231 Cov.: 33 AF XY: 0.711 AC XY: 52895 AN XY: 74344

African (AFR) AF: 0.533 AC: 22084 AN: 41418

American (AMR) AF: 0.750 AC: 11456 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2872 AN: 3470

East Asian (EAS) AF: 0.846 AC: 4386 AN: 5184

South Asian (SAS) AF: 0.743 AC: 3581 AN: 4822

European-Finnish (FIN) AF: 0.775 AC: 8209 AN: 10596

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.775 AC: 52661 AN: 67992

Other (OTH) AF: 0.747 AC: 1576 AN: 2110

Alfa AF: 0.725 Hom.: 5058

Bravo AF: 0.701

Asia WGS AF: 0.765 AC: 2662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.72
PhyloP100		0.73
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: rs10512258; hg19: chr9-101435275;