rs1554709553

Positions:

• chr9-98473185-CTCGAAA-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The ENST00000259455.4(GABBR2):​c.954_959del​(p.Asp318_Phe319del) variant causes a inframe deletion change involving the alteration of a 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 ENST00000259455.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000259455.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.954_959del	p.Asp318_Phe319del	inframe_deletion	6/19	ENST00000259455.4	NP_005449.5
GABBR2	XM_005252316.6	c.180_185del	p.Asp60_Phe61del	inframe_deletion	4/17		XP_005252373.1
GABBR2	XM_017015331.3	c.660_665del	p.Asp220_Phe221del	inframe_deletion	5/18		XP_016870820.1
GABBR2	XM_017015332.3	c.180_185del	p.Asp60_Phe61del	inframe_deletion	3/16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.954_959del	p.Asp318_Phe319del	inframe_deletion	6/19	1	NM_005458.8	ENSP00000259455	P1
GABBR2	ENST00000634919.1	n.732_737del		non_coding_transcript_exon_variant	5/6	5
GABBR2	ENST00000637410.1	n.732_737del		non_coding_transcript_exon_variant	6/19	5
GABBR2	ENST00000477471.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2019

This variant is not present in population databases (ExAC no frequency). This variant, c.954_959delTTTCGA, results in the deletion of 2 amino acids of the GABBR2 protein (p.Asp318_Phe319del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals with a GABBR2-related disease. In summary, this variant has uncertain impact on GABBR2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. -

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: rs1554709553; hg19: chr9-101235467;