NM_005458.8:c.321+12728A>G

Variant names:

• chr9-98695689-T-C
• rs337552
• NM_005458.8:c.321+12728A>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.321+12728A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 152,024 control chromosomes in the GnomAD database, including 38,809 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 0.70 (38809 hom., cov: 32)
• Consequence: GABBR2 NM_005458.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.321+12728A>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+12728A>G		intron_variant	Intron 1 of 18	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000637717.1	c.-64+11555A>G		intron_variant	Intron 1 of 2	5		ENSP00000490789.1

Frequencies

GnomAD3 genomes AF: 0.703 AC: 106810 AN: 151906 Hom.: 38812 Cov.: 32

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.785

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.776

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.738

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

GnomAD4 genome AF: 0.703 AC: 106827 AN: 152024 Hom.: 38809 Cov.: 32 AF XY: 0.704 AC XY: 52307 AN XY: 74296

African (AFR) AF: 0.494 AC: 20445 AN: 41406

American (AMR) AF: 0.758 AC: 11589 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2871 AN: 3468

East Asian (EAS) AF: 0.784 AC: 4056 AN: 5174

South Asian (SAS) AF: 0.720 AC: 3469 AN: 4820

European-Finnish (FIN) AF: 0.776 AC: 8208 AN: 10582

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

European-Non Finnish (NFE) AF: 0.789 AC: 53603 AN: 67970

Other (OTH) AF: 0.737 AC: 1556 AN: 2110

Alfa AF: 0.721 Hom.: 5252

Bravo AF: 0.695

Asia WGS AF: 0.682 AC: 2372 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.042
DANN	Benign	0.41
PhyloP100		-0.41
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: rs337552; hg19: chr9-101457971;