rs1554688978

Positions:

• chr9-98303371-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_005458.8(GABBR2):​c.2282A>G​(p.Gln761Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.26

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GABBR2. . Gene score misZ 4.6253 (greater than the threshold 3.09). Trascript score misZ 4.0975 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 59, neurodevelopmental disorder with poor language and loss of hand skills, atypical Rett syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28855598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.2282A>G	p.Gln761Arg	missense_variant	16/19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.1988A>G	p.Gln663Arg	missense_variant	15/18		XP_016870820.1
GABBR2	XM_005252316.6	c.1508A>G	p.Gln503Arg	missense_variant	14/17		XP_005252373.1
GABBR2	XM_017015332.3	c.1508A>G	p.Gln503Arg	missense_variant	13/16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.2282A>G	p.Gln761Arg	missense_variant	16/19	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000634457.1	c.509A>G	p.Gln170Arg	missense_variant	4/4	5		ENSP00000489352.1
GABBR2	ENST00000637410.1	n.2060A>G		non_coding_transcript_exon_variant	16/19	5
GABBR2	ENST00000636575.1	n.-37A>G		upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Benign	0.46
DEOGEN2	Benign	0.045	T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.8	N;.
REVEL	Uncertain	0.30
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0	B;.
Vest4		0.20
MutPred		0.46		Gain of MoRF binding (P = 0.0097);.;
MVP		0.73
MPC		0.99
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.22
gMVP		0.33

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: rs1554688978; hg19: chr9-101065653; COSMIC: COSV52319084; COSMIC: COSV52319084;