rs771637982

Positions:

• chr9-98290633-C-CGGG

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_005458.8(GABBR2):​c.2776_2777insCCC​(p.Pro925dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00000902 in 1,441,334 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: GABBR2 NM_005458.8 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.53

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005458.8. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR2	NM_005458.8	c.2776_2777insCCC	p.Pro925dup	inframe_insertion	19/19	ENST00000259455.4
GABBR2	XM_005252316.6	c.2002_2003insCCC	p.Pro667dup	inframe_insertion	17/17
GABBR2	XM_017015331.3	c.2482_2483insCCC	p.Pro827dup	inframe_insertion	18/18
GABBR2	XM_017015332.3	c.2002_2003insCCC	p.Pro667dup	inframe_insertion	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR2	ENST00000259455.4	c.2776_2777insCCC	p.Pro925dup	inframe_insertion	19/19	1	NM_005458.8	P1
GABBR2	ENST00000637410.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152008 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000233 AC: 3 AN: 1289326 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 631306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000568

GnomAD4 genome AF: 0.0000658 AC: 10 AN: 152008 Hom.: 1 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74232

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This variant, c.2774_2776dup, results in the insertion of 1 amino acid(s) of the GABBR2 protein (p.Pro925dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs771637982, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GABBR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462136). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771637982; hg19: chr9-101052915;