9-98293840-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005458.8(GABBR2):c.2605A>C(p.Thr869Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T869A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, GABBR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.12056574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR2	NM_005458.8	c.2605A>C	p.Thr869Pro	missense_variant	18/19	ENST00000259455.4
GABBR2	XM_017015331.3	c.2311A>C	p.Thr771Pro	missense_variant	17/18
GABBR2	XM_005252316.6	c.1831A>C	p.Thr611Pro	missense_variant	16/17
GABBR2	XM_017015332.3	c.1831A>C	p.Thr611Pro	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR2	ENST00000259455.4	c.2605A>C	p.Thr869Pro	missense_variant	18/19	1	NM_005458.8	P1
GABBR2	ENST00000637410.1	n.2383A>C		non_coding_transcript_exon_variant	18/19	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460126 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726520

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.98	P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.14
Sift	Benign	0.042	D
Sift4G	Benign	0.087	T
Polyphen		0.17	B
Vest4		0.15
MutPred		0.24		Gain of catalytic residue at T869 (P = 7e-04);
MVP		0.66
MPC		1.1
ClinPred		0.24	T
GERP RS		1.5
Varity_R		0.096
gMVP		0.11

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: rs10985765; hg19: chr9-101056122;