NM_002043.5:c.1298G>A

Variant names:

• chr6-89257770-C-T
• rs61739705
• NM_002043.5:c.1298G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002043.5(GABRR2):​c.1298G>A​(p.Arg433His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,613,924 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. R433C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: GABRR2 NM_002043.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.66
• Publications: 9 publications found

Genes affected

GABRR2 (HGNC:4091): (gamma-aminobutyric acid type A receptor subunit rho2) Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA receptors, which are ligand-gated chloride channels. The protein encoded by this gene is a member of the rho subunit family and is a component of the GABA type A receptor complex. This gene exists on chromosome 6q next to the gene encoding the rho 1 subunit of the GABA type A receptor, in a region thought to be associated with susceptibility for psychiatric disorders and epilepsy. Polymorphisms in this gene may also be associated with alcohol dependence, and general cognitive ability. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009627134).
• BP6: Variant 6-89257770-C-T is Benign according to our data. Variant chr6-89257770-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 730202.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002043.5. 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
	GABRR2	NM_002043.5	MANE Select	c.1298G>A	p.Arg433His	missense	Exon 9 of 9	NP_002034.3	P28476-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GABRR2	ENST00000402938.4	TSL:1 MANE Select	c.1298G>A	p.Arg433His	missense	Exon 9 of 9	ENSP00000386029.4	P28476-1
	GABRR2	ENST00000602432.1	TSL:2	n.1129G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.00373 AC: 567 AN: 152186 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00587

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00352 AC: 883 AN: 251008 AF XY: 0.00403

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00156

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00477 AC: 6976 AN: 1461620 Hom.: 25 Cov.: 30 AF XY: 0.00479 AC XY: 3484 AN XY: 727084

African (AFR) AF: 0.00158 AC: 53 AN: 33480

American (AMR) AF: 0.00159 AC: 71 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00203 AC: 175 AN: 86246

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53400

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.00560 AC: 6227 AN: 1111798

Other (OTH) AF: 0.00459 AC: 277 AN: 60372

GnomAD4 genome AF: 0.00372 AC: 566 AN: 152304 Hom.: 2 Cov.: 31 AF XY: 0.00369 AC XY: 275 AN XY: 74474

African (AFR) AF: 0.00216 AC: 90 AN: 41574

American (AMR) AF: 0.00261 AC: 40 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00587 AC: 399 AN: 68022

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00478 Hom.: 9

Bravo AF: 0.00388

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00366 AC: 444

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00789

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.85
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.32	T
REVEL	Benign	0.072
Sift4G	Benign	0.59	T
Vest4		0.12
MVP		0.90
MPC		0.19
ClinPred		0.0071	T
GERP RS		4.1
Varity_R		0.047
gMVP		0.64
Mutation Taster		=98/2	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: rs61739705; hg19: chr6-89967489; COSMIC: COSV101298996;