9-98708682-G-A

Variant names:

• chr9-98708682-G-A
• rs1054346747
• NM_005458.8:c.56C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_005458.8(GABBR2):​c.56C>T​(p.Pro19Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000398 in 1,080,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.17
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22733957).
• BP6: Variant 9-98708682-G-A is Benign according to our data. Variant chr9-98708682-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 571315.
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005458.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.56C>T	p.Pro19Leu	missense	Exon 1 of 19	NP_005449.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.56C>T	p.Pro19Leu	missense	Exon 1 of 19	ENSP00000259455.2

Frequencies

GnomAD3 genomes AF: 0.0000340 AC: 5 AN: 147038 Hom.: 0 Cov.: 32

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000757

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000407 AC: 38 AN: 933290 Hom.: 0 Cov.: 21 AF XY: 0.0000500 AC XY: 22 AN XY: 439952

African (AFR) AF: 0.00 AC: 0 AN: 18128

American (AMR) AF: 0.00 AC: 0 AN: 4002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8264

East Asian (EAS) AF: 0.00 AC: 0 AN: 11510

South Asian (SAS) AF: 0.00 AC: 0 AN: 18166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2134

European-Non Finnish (NFE) AF: 0.0000460 AC: 38 AN: 826632

Other (OTH) AF: 0.00 AC: 0 AN: 33460

GnomAD4 genome AF: 0.0000340 AC: 5 AN: 147038 Hom.: 0 Cov.: 32 AF XY: 0.0000280 AC XY: 2 AN XY: 71514

African (AFR) AF: 0.00 AC: 0 AN: 40910

American (AMR) AF: 0.00 AC: 0 AN: 14800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000757 AC: 5 AN: 66086

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy, 59 (1)
-	-	1	Epileptic encephalopathy (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.010	N
REVEL	Benign	0.15
Sift	Benign	0.64	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.064	B
Vest4		0.24
MutPred		0.31		Loss of glycosylation at P19 (P = 5e-04)
MVP		0.73
MPC		1.4
ClinPred		0.50	D
GERP RS		1.6
PromoterAI		-0.038	Neutral
Varity_R		0.073
gMVP		0.32
Mutation Taster		=82/18	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: rs1054346747; hg19: chr9-101470964;