rs34701111

Variant names:

• chr9-98293826-T-C
• rs34701111
• NM_005458.8:c.2619A>G

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.2619A>G​(p.Arg873Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,610,204 control chromosomes in the GnomAD database, including 3,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R873R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.084 (1826 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (1506 hom.)
• Consequence: GABBR2 NM_005458.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.97
• Publications: 3 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)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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=-0.54).
• BP6: Variant 9-98293826-T-C is Benign according to our data. Variant chr9-98293826-T-C is described in ClinVar as Benign. ClinVar VariationId is 462133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 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.2619A>G	p.Arg873Arg	synonymous	Exon 18 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.2619A>G	p.Arg873Arg	synonymous	Exon 18 of 19	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.2553A>G	p.Arg851Arg	synonymous	Exon 17 of 18	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.2538A>G	p.Arg846Arg	synonymous	Exon 17 of 18	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12801 AN: 152180 Hom.: 1826 Cov.: 33

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0214 AC: 5391 AN: 251330 AF XY: 0.0155

Gnomad AFR exome AF: 0.299

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00802 AC: 11691 AN: 1457906 Hom.: 1506 Cov.: 28 AF XY: 0.00682 AC XY: 4950 AN XY: 725676

African (AFR) AF: 0.291 AC: 9540 AN: 32818

American (AMR) AF: 0.0134 AC: 600 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000627 AC: 54 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5760

European-Non Finnish (NFE) AF: 0.000324 AC: 359 AN: 1108980

Other (OTH) AF: 0.0177 AC: 1064 AN: 60252

GnomAD4 genome AF: 0.0842 AC: 12818 AN: 152298 Hom.: 1826 Cov.: 33 AF XY: 0.0808 AC XY: 6022 AN XY: 74496

African (AFR) AF: 0.294 AC: 12198 AN: 41516

American (AMR) AF: 0.0284 AC: 434 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68038

Other (OTH) AF: 0.0577 AC: 122 AN: 2116

Alfa AF: 0.0755 Hom.: 1228

Bravo AF: 0.0973

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.1
DANN	Benign	0.67
PhyloP100		3.0
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: rs34701111; hg19: chr9-101056108;