NM_005458.8:c.2743G>T

Variant names:

• chr9-98290667-C-A
• rs1554687394
• NM_005458.8:c.2743G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005458.8(GABBR2):​c.2743G>T​(p.Val915Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000151 in 1,324,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.75
• 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)
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1470288).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	NM_005458.8	MANE Select	c.2743G>T	p.Val915Phe	missense	Exon 19 of 19	NP_005449.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABBR2	ENST00000259455.4	TSL:1 MANE Select	c.2743G>T	p.Val915Phe	missense	Exon 19 of 19	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.2677G>T	p.Val893Phe	missense	Exon 18 of 18	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.2662G>T	p.Val888Phe	missense	Exon 18 of 18	ENSP00000617435.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1324086 Hom.: 0 Cov.: 31 AF XY: 0.00000306 AC XY: 2 AN XY: 653058

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26082

American (AMR) AF: 0.00 AC: 0 AN: 17230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21628

East Asian (EAS) AF: 0.00 AC: 0 AN: 31176

South Asian (SAS) AF: 0.00 AC: 0 AN: 61946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5162

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1055860

Other (OTH) AF: 0.00 AC: 0 AN: 54480

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epileptic encephalopathy (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.23
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.021	D
Polyphen		0.072	B
Vest4		0.18
MutPred		0.14		Loss of sheet (P = 0.0457)
MVP		0.36
MPC		1.3
ClinPred		0.83	D
GERP RS		5.5
Varity_R		0.23
gMVP		0.36
Mutation Taster		=86/14	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: rs1554687394; hg19: chr9-101052949;