9-98454172-C-G

Variant names:

• chr9-98454172-C-G
• rs759044661
• NM_005458.8:c.1045G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005458.8(GABBR2):​c.1045G>C​(p.Val349Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABBR2	NM_005458.8	c.1045G>C	p.Val349Leu	missense_variant	Exon 7 of 19	ENST00000259455.4	NP_005449.5
GABBR2	XM_017015331.3	c.751G>C	p.Val251Leu	missense_variant	Exon 6 of 18		XP_016870820.1
GABBR2	XM_005252316.6	c.271G>C	p.Val91Leu	missense_variant	Exon 5 of 17		XP_005252373.1
GABBR2	XM_017015332.3	c.271G>C	p.Val91Leu	missense_variant	Exon 4 of 16		XP_016870821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABBR2	ENST00000259455.4	c.1045G>C	p.Val349Leu	missense_variant	Exon 7 of 19	1	NM_005458.8	ENSP00000259455.2
GABBR2	ENST00000634919.1	n.823G>C		non_coding_transcript_exon_variant	Exon 6 of 6	5
GABBR2	ENST00000637410.1	n.823G>C		non_coding_transcript_exon_variant	Exon 7 of 19	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Benign	0.97	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.71	N
REVEL	Uncertain	0.52
Sift	Benign	0.35	T
Sift4G	Benign	0.72	T
Polyphen		1.0	D
Vest4		0.33
MutPred		0.55		Loss of ubiquitination at K353 (P = 0.0787);
MVP		0.86
MPC		0.91
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.53
gMVP		0.72

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: rs759044661; hg19: chr9-101216454;