6-89257770-C-T

Position:

• chr6-89257770-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: GABRR2 NM_002043.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.66

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]

GABRR2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 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 [Likely_benign]. Clinvar id is 730202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GABRR2	NM_002043.5	c.1298G>A	p.Arg433His	missense_variant	9/9	ENST00000402938.4	NP_002034.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GABRR2	ENST00000402938.4	c.1298G>A	p.Arg433His	missense_variant	9/9	1	NM_002043.5	ENSP00000386029.4
GABRR2	ENST00000602432.1	n.1129G>A		non_coding_transcript_exon_variant	6/6	2

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

GnomAD3 exomes AF: 0.00352 AC: 883 AN: 251008 Hom.: 3 AF XY: 0.00403 AC XY: 547 AN XY: 135658

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 SAS exome AF: 0.00245

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

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.00145

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00560

Gnomad4 OTH exome AF: 0.00459

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

Gnomad4 AFR AF: 0.00216

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00587

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00508 Hom.: 7

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

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	GABRR2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

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
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

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: rs61739705; hg19: chr6-89967489; COSMIC: COSV101298996;