rs35449008

Variant names:

• chr9-98542020-A-G
• rs35449008
• NM_005458.8:c.483T>C

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.483T>C​(p.Pro161Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0368 in 1,614,052 control chromosomes in the GnomAD database, including 1,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (561 hom., cov: 33)
  • Exomes 𝑓: 0.034 (1211 hom.)
• Consequence: GABBR2 NM_005458.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.664
• Publications: 4 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=-0.65).
• BP6: Variant 9-98542020-A-G is Benign according to our data. Variant chr9-98542020-A-G is described in ClinVar as Benign. ClinVar VariationId is 462139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.483T>C	p.Pro161Pro	synonymous_variant	Exon 3 of 19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.189T>C	p.Pro63Pro	synonymous_variant	Exon 2 of 18		XP_016870820.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.483T>C	p.Pro161Pro	synonymous_variant	Exon 3 of 19	1	NM_005458.8	ENSP00000259455.2

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9963 AN: 152196 Hom.: 559 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0473

GnomAD2 exomes AF: 0.0339 AC: 8510 AN: 250898 AF XY: 0.0312

Gnomad AFR exome AF: 0.159

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0346

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0338 AC: 49468 AN: 1461738 Hom.: 1211 Cov.: 31 AF XY: 0.0329 AC XY: 23903 AN XY: 727170

African (AFR) AF: 0.159 AC: 5335 AN: 33474

American (AMR) AF: 0.0186 AC: 831 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 543 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0109 AC: 938 AN: 86248

European-Finnish (FIN) AF: 0.0335 AC: 1791 AN: 53416

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5768

European-Non Finnish (NFE) AF: 0.0339 AC: 37743 AN: 1111906

Other (OTH) AF: 0.0355 AC: 2143 AN: 60392

GnomAD4 genome AF: 0.0656 AC: 9988 AN: 152314 Hom.: 561 Cov.: 33 AF XY: 0.0645 AC XY: 4801 AN XY: 74472

African (AFR) AF: 0.159 AC: 6618 AN: 41540

American (AMR) AF: 0.0322 AC: 493 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4834

European-Finnish (FIN) AF: 0.0369 AC: 392 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0333 AC: 2267 AN: 68040

Other (OTH) AF: 0.0468 AC: 99 AN: 2114

Alfa AF: 0.0468 Hom.: 609

Bravo AF: 0.0697

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0297

EpiControl AF: 0.0295

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Epileptic encephalopathy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.1
DANN	Benign	0.72
PhyloP100		-0.66
Mutation Taster		=90/10	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: rs35449008; hg19: chr9-101304302;