rs144313756

Positions:

• chr9-98388910-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_005458.8(GABBR2):​c.1473C>T​(p.Leu491=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000844 in 1,613,668 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00085 (2 hom.)
• Consequence: GABBR2 NM_005458.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0800

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 9-98388910-G-A is Benign according to our data. Variant chr9-98388910-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 462124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.08 with no splicing effect.
• BS2: High AC in GnomAd4 at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.1473C>T	p.Leu491=	synonymous_variant	10/19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1179C>T	p.Leu393=	synonymous_variant	9/18		XP_016870820.1
GABBR2	XM_005252316.6	c.699C>T	p.Leu233=	synonymous_variant	8/17		XP_005252373.1
GABBR2	XM_017015332.3	c.699C>T	p.Leu233=	synonymous_variant	7/16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.1473C>T	p.Leu491=	synonymous_variant	10/19	1	NM_005458.8	ENSP00000259455	P1
GABBR2	ENST00000637410.1	n.1251C>T		non_coding_transcript_exon_variant	10/19	5
GABBR2	ENST00000634314.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152140 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000931 AC: 234 AN: 251382 Hom.: 1 AF XY: 0.000898 AC XY: 122 AN XY: 135848

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00704

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000923

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000847 AC: 1238 AN: 1461410 Hom.: 2 Cov.: 30 AF XY: 0.000857 AC XY: 623 AN XY: 727022

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00635

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000836

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000814 AC: 124 AN: 152258 Hom.: 0 Cov.: 31 AF XY: 0.000833 AC XY: 62 AN XY: 74454

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000929

EpiCase AF: 0.000927

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	GABBR2: BP4, BP7, BS1 -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

GABBR2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2019

This variant is classified as 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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.6
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: rs144313756; hg19: chr9-101151192;