6-89264443-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002043.5(GABRR2):c.1055A>G(p.Gln352Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00419 in 1,613,984 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (22 hom.)
• Consequence: GABRR2 NM_002043.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.23

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006909609).
• BP6: Variant 6-89264443-T-C is Benign according to our data. Variant chr6-89264443-T-C is described in ClinVar as [Benign]. Clinvar id is 776595.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GABRR2	NM_002043.5	c.1055A>G	p.Gln352Arg	missense_variant	8/9	ENST00000402938.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GABRR2	ENST00000402938.4	c.1055A>G	p.Gln352Arg	missense_variant	8/9	1	NM_002043.5	P1
GABRR2	ENST00000602432.1	n.886A>G		non_coding_transcript_exon_variant	5/6	2

Frequencies

GnomAD3 genomes AF: 0.00266 AC: 404 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00858

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00398

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00342 AC: 857 AN: 250766 Hom.: 5 AF XY: 0.00314 AC XY: 425 AN XY: 135486

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00966

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.00310

GnomAD4 exome AF: 0.00435 AC: 6360 AN: 1461718 Hom.: 22 Cov.: 32 AF XY: 0.00416 AC XY: 3024 AN XY: 727172

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.00506

Gnomad4 OTH exome AF: 0.00257

GnomAD4 genome AF: 0.00265 AC: 404 AN: 152266 Hom.: 0 Cov.: 31 AF XY: 0.00257 AC XY: 191 AN XY: 74452

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00858

Gnomad4 NFE AF: 0.00398

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00333 Hom.: 3

Bravo AF: 0.00196

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00396 AC: 481

EpiCase AF: 0.00338

EpiControl AF: 0.00403

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.066	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
REVEL	Benign	0.087
Sift4G	Benign	0.68	T
Vest4		0.32
MVP		0.87
MPC		0.16
ClinPred		0.022	T
GERP RS		5.9
Varity_R		0.29
gMVP		0.59

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: rs117866541; hg19: chr6-89974162; COSMIC: COSV68764697;