chr9-98290643-C-A

Variant names:

• chr9-98290643-C-A
• rs758345055
• NM_005458.8:c.2767G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_005458.8(GABBR2):​c.2767G>T​(p.Ala923Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000207 in 1,447,654 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A923V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: GABBR2 NM_005458.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.24
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0855262).
• BP6: Variant 9-98290643-C-A is Benign according to our data. Variant chr9-98290643-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3340554.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2767G>T	p.Ala923Ser	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.2767G>T	p.Ala923Ser	missense	Exon 19 of 19	ENSP00000259455.2	O75899
	GABBR2	ENST00000931526.1		c.2701G>T	p.Ala901Ser	missense	Exon 18 of 18	ENSP00000601585.1
	GABBR2	ENST00000947376.1		c.2686G>T	p.Ala896Ser	missense	Exon 18 of 18	ENSP00000617435.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152022 Hom.: 0 Cov.: 31

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295632 Hom.: 0 Cov.: 31 AF XY: 0.00000157 AC XY: 1 AN XY: 635316

African (AFR) AF: 0.00 AC: 0 AN: 25820

American (AMR) AF: 0.00 AC: 0 AN: 16984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30906

South Asian (SAS) AF: 0.00 AC: 0 AN: 58218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4958

European-Non Finnish (NFE) AF: 9.65e-7 AC: 1 AN: 1036064

Other (OTH) AF: 0.00 AC: 0 AN: 53070

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152022 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74252

African (AFR) AF: 0.00 AC: 0 AN: 41396

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000605 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.28
Sift	Benign	0.19	T
Sift4G	Benign	0.41	T
Polyphen		0.016	B
Vest4		0.057
MutPred		0.097		Gain of relative solvent accessibility (P = 0.005)
MVP		0.44
MPC		0.83
ClinPred		0.49	T
GERP RS		5.5
Varity_R		0.097
gMVP		0.25
Mutation Taster		=74/26	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: rs758345055; hg19: chr9-101052925;