9-98454172-C-G

Position:

• chr9-98454172-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

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]

GABBR2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

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

Ensembl

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