rs2304389

Positions:

• chr9-98306298-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005458.8(GABBR2):​c.2052C>T​(p.Pro684Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 1,613,292 control chromosomes in the GnomAD database, including 22,495 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2178 hom., cov: 33)
  • Exomes 𝑓: 0.16 (20317 hom.)
• Consequence: GABBR2 NM_005458.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.14

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-98306298-G-A is Benign according to our data. Variant chr9-98306298-G-A is described in ClinVar as [Benign]. Clinvar id is 1167956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.2052C>T	p.Pro684Pro	synonymous_variant	15/19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1758C>T	p.Pro586Pro	synonymous_variant	14/18		XP_016870820.1
GABBR2	XM_005252316.6	c.1278C>T	p.Pro426Pro	synonymous_variant	13/17		XP_005252373.1
GABBR2	XM_017015332.3	c.1278C>T	p.Pro426Pro	synonymous_variant	12/16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.2052C>T	p.Pro684Pro	synonymous_variant	15/19	1	NM_005458.8	ENSP00000259455.2

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25174 AN: 152084 Hom.: 2181 Cov.: 33

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.170 AC: 42575 AN: 251022 Hom.: 3815 AF XY: 0.172 AC XY: 23361 AN XY: 135692

Gnomad AFR exome AF: 0.172

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.166

Gnomad SAS exome AF: 0.218

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.164 AC: 240257 AN: 1461090 Hom.: 20317 Cov.: 33 AF XY: 0.166 AC XY: 120679 AN XY: 726900

Gnomad4 AFR exome AF: 0.170

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.174

Gnomad4 SAS exome AF: 0.212

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.161

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.165 AC: 25177 AN: 152202 Hom.: 2178 Cov.: 33 AF XY: 0.165 AC XY: 12267 AN XY: 74418

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.186

Alfa AF: 0.165 Hom.: 2791

Bravo AF: 0.169

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.171

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

Neurodevelopmental disorder with poor language and loss of hand skills Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 59 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.77

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: rs2304389; hg19: chr9-101068580; COSMIC: COSV52295707; COSMIC: COSV52295707;