Genetic Variant NM_002043.5:c.249A>G (chr6-89271694-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_002043.5(GABRR2):c.249A>G(p.Val83Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 1,610,554 control chromosomes in the GnomAD database, including 304,709 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 0.65 ( 33103 hom., cov: 31)

Exomes 𝑓: 0.61 ( 271606 hom. )

Consequence

GABRR2
NM_002043.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.114

Publications

18 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP7

Synonymous conserved (PhyloP=-0.114 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABRR2	NM_002043.5 link	c.249A>G	p.Val83Val	synonymous_variant	Exon 3 of 9	ENST00000402938.4	NP_002034.3	P28476-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABRR2	ENST00000402938.4 link	c.249A>G	p.Val83Val	synonymous_variant	Exon 3 of 9	1	NM_002043.5	ENSP00000386029.4		P28476-1
GABRR2	ENST00000602808.1 link	n.383A>G		non_coding_transcript_exon_variant	Exon 3 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.655

AC:

99489

AN:

151936

Hom.:

33053

Cov.:

show subpopulations

Gnomad AFR

AF:

0.779

Gnomad AMI

AF:

0.580

Gnomad AMR

AF:

0.605

Gnomad ASJ

AF:

0.554

Gnomad EAS

AF:

0.707

Gnomad SAS

AF:

0.679

Gnomad FIN

AF:

0.621

Gnomad MID

AF:

0.583

Gnomad NFE

AF:

0.597

Gnomad OTH

AF:

0.656

GnomAD2 exomes

AF:

0.622

AC:

153083

AN:

245940

AF XY:

0.622

show subpopulations

Gnomad AFR exome

AF:

0.785

Gnomad AMR exome

AF:

0.590

Gnomad ASJ exome

AF:

0.539

Gnomad EAS exome

AF:

0.695

Gnomad FIN exome

AF:

0.620

Gnomad NFE exome

AF:

0.593

Gnomad OTH exome

AF:

0.599

GnomAD4 exome

AF:

0.608

AC:

887318

AN:

1458500

Hom.:

271606

Cov.:

AF XY:

0.609

AC XY:

441468

AN XY:

725248

show subpopulations

African (AFR)

AF:

0.789

AC:

26385

AN:

33428

American (AMR)

AF:

0.590

AC:

26200

AN:

44394

Ashkenazi Jewish (ASJ)

AF:

0.544

AC:

14182

AN:

26074

East Asian (EAS)

AF:

0.705

AC:

27935

AN:

39598

South Asian (SAS)

AF:

0.674

AC:

57790

AN:

85748

European-Finnish (FIN)

AF:

0.623

AC:

33094

AN:

53106

Middle Eastern (MID)

AF:

0.551

AC:

3178

AN:

5766

European-Non Finnish (NFE)

AF:

0.596

AC:

661194

AN:

1110118

Other (OTH)

AF:

0.620

AC:

37360

AN:

60268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

17164

34328

51493

68657

85821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18178

36356

54534

72712

90890

<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:

0.655

AC:

99591

AN:

152054

Hom.:

33103

Cov.:

AF XY:

0.656

AC XY:

48762

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.779

AC:

32296

AN:

41470

American (AMR)

AF:

0.605

AC:

9253

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.554

AC:

1921

AN:

3470

East Asian (EAS)

AF:

0.707

AC:

3650

AN:

5164

South Asian (SAS)

AF:

0.678

AC:

3271

AN:

4824

European-Finnish (FIN)

AF:

0.621

AC:

6563

AN:

10574

Middle Eastern (MID)

AF:

0.589

AC:

172

AN:

292

European-Non Finnish (NFE)

AF:

0.597

AC:

40549

AN:

67950

Other (OTH)

AF:

0.658

AC:

1388

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1751

3501

5252

7002

8753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

794

1588

2382

3176

3970

<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:

0.612

Hom.:

44274

Bravo

AF:

0.657

Asia WGS

AF:

0.718

AC:

2499

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

-0.11

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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