Genetic Variant NM_002808.5:c.939G>T (chr3-184302754-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002808.5(PSMD2):c.939G>T(p.Glu313Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,614,012 control chromosomes in the GnomAD database, including 18,520 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1259 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17261 hom. )

Consequence

PSMD2
NM_002808.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.440

Publications

39 publications found

Variant links:

Genes affected

PSMD2 (HGNC:9559): (proteasome 26S subunit ubiquitin receptor, non-ATPase 2) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes one of the non-ATPase subunits of the 19S regulator lid. In addition to participation in proteasome function, this subunit may also participate in the TNF signalling pathway since it interacts with the tumor necrosis factor type 1 receptor. A pseudogene has been identified on chromosome 1. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

PSMD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0014640391).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMD2	NM_002808.5 link	c.939G>T	p.Glu313Asp	missense_variant	Exon 7 of 21	ENST00000310118.9	NP_002799.3	Q13200-1
PSMD2	NM_001278708.2 link	c.549G>T	p.Glu183Asp	missense_variant	Exon 5 of 19		NP_001265637.1	Q13200-3
PSMD2	NM_001278709.2 link	c.462G>T	p.Glu154Asp	missense_variant	Exon 5 of 19		NP_001265638.1	Q13200-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMD2	ENST00000310118.9 link	c.939G>T	p.Glu313Asp	missense_variant	Exon 7 of 21	1	NM_002808.5	ENSP00000310129.4		Q13200-1

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17248

AN:

152010

Hom.:

1260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0285

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.129

Gnomad EAS

AF:

0.0240

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.187

Gnomad MID

AF:

0.0823

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.112

GnomAD2 exomes

AF:

0.133

AC:

33536

AN:

251432

AF XY:

0.137

show subpopulations

Gnomad AFR exome

AF:

0.0246

Gnomad AMR exome

AF:

0.132

Gnomad ASJ exome

AF:

0.134

Gnomad EAS exome

AF:

0.0269

Gnomad FIN exome

AF:

0.191

Gnomad NFE exome

AF:

0.156

Gnomad OTH exome

AF:

0.140

GnomAD4 exome

AF:

0.150

AC:

219407

AN:

1461882

Hom.:

17261

Cov.:

AF XY:

0.151

AC XY:

109565

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.0236

AC:

790

AN:

33480

American (AMR)

AF:

0.126

AC:

5635

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.133

AC:

3475

AN:

26136

East Asian (EAS)

AF:

0.0166

AC:

661

AN:

39700

South Asian (SAS)

AF:

0.130

AC:

11214

AN:

86258

European-Finnish (FIN)

AF:

0.192

AC:

10252

AN:

53412

Middle Eastern (MID)

AF:

0.103

AC:

594

AN:

5766

European-Non Finnish (NFE)

AF:

0.161

AC:

178733

AN:

1112010

Other (OTH)

AF:

0.133

AC:

8053

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

11073

22146

33220

44293

55366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6238

12476

18714

24952

31190

<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:

0.113

AC:

17242

AN:

152130

Hom.:

1259

Cov.:

AF XY:

0.114

AC XY:

8469

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0284

AC:

1181

AN:

41514

American (AMR)

AF:

0.115

AC:

1757

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.129

AC:

448

AN:

3468

East Asian (EAS)

AF:

0.0245

AC:

127

AN:

5190

South Asian (SAS)

AF:

0.127

AC:

614

AN:

4816

European-Finnish (FIN)

AF:

0.187

AC:

1982

AN:

10574

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.159

AC:

10785

AN:

67980

Other (OTH)

AF:

0.111

AC:

233

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

751

1501

2252

3002

3753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<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:

0.138

Hom.:

2858

Bravo

AF:

0.103

TwinsUK

AF:

0.157

AC:

582

ALSPAC

AF:

0.159

AC:

613

ESP6500AA

AF:

0.0297

AC:

131

ESP6500EA

AF:

0.161

AC:

1385

ExAC

AF:

0.131

AC:

15892

Asia WGS

AF:

0.0530

AC:

183

AN:

3478

EpiCase

AF:

0.156

EpiControl

AF:

0.154

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.74

CADD

Benign

9.0

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.080

T;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.73

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

D;D;D

MetaRNN

Benign

0.0015

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.39

N;.;.

PhyloP100

0.44

PrimateAI

Uncertain

0.78

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.87

T;T;T

Sift4G

Benign

0.91

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.043

MutPred

0.17

Gain of glycosylation at Y314 (P = 0.0167);.;.;

MPC

0.62

ClinPred

0.00027

GERP RS

1.3

Varity_R

0.17

gMVP

0.13

Mutation Taster

=99/1

polymorphism (auto)

(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