9-98290631-G-GGCGGGGGCTGGCGGTGGGGCTGAC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_005458.8(GABBR2):c.2778_2779insGTCAGCCCCACCGCCAGCCCCCGC(p.Val919_Arg926dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GABBR2 NM_005458.8 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005458.8.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR2	NM_005458.8	c.2778_2779insGTCAGCCCCACCGCCAGCCCCCGC	p.Val919_Arg926dup	inframe_insertion	19/19	ENST00000259455.4
GABBR2	XM_005252316.6	c.2004_2005insGTCAGCCCCACCGCCAGCCCCCGC	p.Val661_Arg668dup	inframe_insertion	17/17
GABBR2	XM_017015331.3	c.2484_2485insGTCAGCCCCACCGCCAGCCCCCGC	p.Val821_Arg828dup	inframe_insertion	18/18
GABBR2	XM_017015332.3	c.2004_2005insGTCAGCCCCACCGCCAGCCCCCGC	p.Val661_Arg668dup	inframe_insertion	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR2	ENST00000259455.4	c.2778_2779insGTCAGCCCCACCGCCAGCCCCCGC	p.Val919_Arg926dup	inframe_insertion	19/19	1	NM_005458.8	P1
GABBR2	ENST00000637410.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Jan 11, 2024

This variant, c.2755_2778dup, results in the insertion of 8 amino acid(s) of the GABBR2 protein (p.Val919_Arg926dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (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: 1427254). 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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-101052913;