rs780232385

chr9-98311213-AAG-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_005458.8(GABBR2):c.1894-10_1894-9del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000281 in 1,581,356 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: GABBR2 NM_005458.8 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.31

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP6: Variant 9-98311213-AAG-A is Benign according to our data. Variant chr9-98311213-AAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 531095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR2	NM_005458.8	c.1894-10_1894-9del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000259455.4
GABBR2	XM_005252316.6	c.1120-10_1120-9del		splice_polypyrimidine_tract_variant, intron_variant
GABBR2	XM_017015331.3	c.1600-10_1600-9del		splice_polypyrimidine_tract_variant, intron_variant
GABBR2	XM_017015332.3	c.1120-10_1120-9del		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR2	ENST00000259455.4	c.1894-10_1894-9del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_005458.8	P1
GABBR2	ENST00000634457.1	c.232-4870_232-4869del		intron_variant		5
GABBR2	ENST00000635462.1	n.389-10_389-9del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2
GABBR2	ENST00000637410.1	n.1672-10_1672-9del		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000228 AC: 57 AN: 250452 Hom.: 0 AF XY: 0.000214 AC XY: 29 AN XY: 135304

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000287 AC: 410 AN: 1429098 Hom.: 0 AF XY: 0.000251 AC XY: 179 AN XY: 713186

Gnomad4 AFR exome AF: 0.0000609

Gnomad4 AMR exome AF: 0.000695

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.000320

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74456

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000272

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epileptic encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2021

- -

GABBR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs780232385; hg19: chr9-101073495;