Genetic Variant NM_002043.5:c.135T>C (chr6-89299844-A-G) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP7BS2

The NM_002043.5(GABRR2):c.135T>C(p.Leu45Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,234 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 6 hom. )

Consequence

GABRR2
NM_002043.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.39

Publications

2 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP7

Synonymous conserved (PhyloP=-2.39 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRR2	NM_002043.5 link	c.135T>C	p.Leu45Leu	synonymous_variant	Exon 2 of 9	ENST00000402938.4	NP_002034.3
GABRR2	XM_047418599.1 link	c.210T>C	p.Leu70Leu	synonymous_variant	Exon 2 of 10		XP_047274555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRR2	ENST00000402938.4 link	c.135T>C	p.Leu45Leu	synonymous_variant	Exon 2 of 9	1	NM_002043.5	ENSP00000386029.4
GABRR2	ENST00000602808.1 link	n.269T>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00123

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00158

AC:

397

AN:

251164

AF XY:

0.00155

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00249

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00160

AC:

2335

AN:

1460918

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1221

AN XY:

726824

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33454

American (AMR)

AF:

0.00177

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000510

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00103

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00186

AC:

2063

AN:

1111146

Other (OTH)

AF:

0.00111

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

106

211

317

422

528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00139

AC:

212

AN:

152316

Hom.:

Cov.:

AF XY:

0.00117

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41568

American (AMR)

AF:

0.000915

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00243

AC:

165

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00144

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00261

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.0050

(source)

DANN

Benign

0.43

PhyloP100

-2.4

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over