rs1554688978

Variant names:

• chr9-98303371-T-C
• rs1554688978
• NM_005458.8:c.2282A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q761Q) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 59

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with poor language and loss of hand skills

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28855598).

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.2282A>G	p.Gln761Arg	missense_variant	Exon 16 of 19	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000634457.1	c.509A>G	p.Gln170Arg	missense_variant	Exon 4 of 4	5		ENSP00000489352.1
GABBR2	ENST00000637410.1	n.2060A>G		non_coding_transcript_exon_variant	Exon 16 of 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

Jul 11, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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;.
PhyloP100		6.3
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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

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