rs79226810

chr9-98293810-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_005458.8(GABBR2):c.2635A>G(p.Ile879Val) variant causes a missense change. The variant allele was found at a frequency of 0.000151 in 1,592,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I879T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.95

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, GABBR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.062741846).
• BP6: Variant 9-98293810-T-C is Benign according to our data. Variant chr9-98293810-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 567007.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABBR2	NM_005458.8	c.2635A>G	p.Ile879Val	missense_variant	18/19	ENST00000259455.4
GABBR2	XM_017015331.3	c.2341A>G	p.Ile781Val	missense_variant	17/18
GABBR2	XM_005252316.6	c.1861A>G	p.Ile621Val	missense_variant	16/17
GABBR2	XM_017015332.3	c.1861A>G	p.Ile621Val	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABBR2	ENST00000259455.4	c.2635A>G	p.Ile879Val	missense_variant	18/19	1	NM_005458.8	P1
GABBR2	ENST00000637410.1	n.2413A>G		non_coding_transcript_exon_variant	18/19	5

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251320 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000158 AC: 227 AN: 1440634 Hom.: 0 Cov.: 27 AF XY: 0.000141 AC XY: 101 AN XY: 718230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.000198

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000112 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Epileptic encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	17
Dann	Uncertain	0.98
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.85	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.18
Sift	Benign	0.032	D
Sift4G	Benign	0.12	T
Polyphen		0.0	B
Vest4		0.23
MVP		0.40
MPC		0.76
ClinPred		0.091	T
GERP RS		4.0
Varity_R		0.039
gMVP		0.14

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: rs79226810; hg19: chr9-101056092;