rs2304389

Variant names:

• chr9-98306298-G-A
• rs2304389
• NM_005458.8:c.2052C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 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 -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 VariationId 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.

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.2052C>T	p.Pro684Pro	synonymous	Exon 15 of 19	NP_005449.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.2052C>T	p.Pro684Pro	synonymous	Exon 15 of 19	ENSP00000259455.2
	GABBR2	ENST00000931526.1		c.1986C>T	p.Pro662Pro	synonymous	Exon 14 of 18	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.1971C>T	p.Pro657Pro	synonymous	Exon 14 of 18	ENSP00000617435.1

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

GnomAD2 exomes AF: 0.170 AC: 42575 AN: 251022 AF XY: 0.172

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 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

African (AFR) AF: 0.170 AC: 5675 AN: 33464

American (AMR) AF: 0.193 AC: 8617 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3398 AN: 26128

East Asian (EAS) AF: 0.174 AC: 6920 AN: 39696

South Asian (SAS) AF: 0.212 AC: 18289 AN: 86218

European-Finnish (FIN) AF: 0.134 AC: 7132 AN: 53412

Middle Eastern (MID) AF: 0.267 AC: 1538 AN: 5766

European-Non Finnish (NFE) AF: 0.161 AC: 178396 AN: 1111350

Other (OTH) AF: 0.170 AC: 10292 AN: 60372

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

African (AFR) AF: 0.171 AC: 7108 AN: 41528

American (AMR) AF: 0.191 AC: 2923 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 454 AN: 3470

East Asian (EAS) AF: 0.173 AC: 896 AN: 5172

South Asian (SAS) AF: 0.211 AC: 1017 AN: 4826

European-Finnish (FIN) AF: 0.133 AC: 1413 AN: 10594

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10738 AN: 68006

Other (OTH) AF: 0.186 AC: 393 AN: 2112

Alfa AF: 0.163 Hom.: 6232

Bravo AF: 0.169

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.171

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Developmental and epileptic encephalopathy, 59 (1)
-	-	1	Epileptic encephalopathy (1)
-	-	1	Neurodevelopmental disorder with poor language and loss of hand skills (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.77
PhyloP100		-2.1
Mutation Taster		=99/1	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: rs2304389; hg19: chr9-101068580; COSMIC: COSV52295707; COSMIC: COSV52295707;