3-184301537-C-G

Variant names:

• chr3-184301537-C-G
• rs142662907
• NM_002808.5:c.358C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002808.5(PSMD2):​c.358C>G​(p.Arg120Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R120C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMD2 NM_002808.5 missense, splice_region
• Scores: Splicing: ADA: 0.009946
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.71
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35355678).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002808.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD2	NM_002808.5	MANE Select	c.358C>G	p.Arg120Gly	missense splice_region	Exon 4 of 21	NP_002799.3
	PSMD2	NM_001278708.2		c.-33C>G		splice_region	Exon 2 of 19	NP_001265637.1	Q13200-3
	PSMD2	NM_001278709.2		c.-109C>G		splice_region	Exon 2 of 19	NP_001265638.1	Q13200-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMD2	ENST00000310118.9	TSL:1 MANE Select	c.358C>G	p.Arg120Gly	missense splice_region	Exon 4 of 21	ENSP00000310129.4	Q13200-1
	PSMD2	ENST00000926941.1		c.358C>G	p.Arg120Gly	missense splice_region	Exon 4 of 21	ENSP00000597000.1
	PSMD2	ENST00000926945.1		c.358C>G	p.Arg120Gly	missense splice_region	Exon 4 of 21	ENSP00000597004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000422 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.042
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.7
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.020	B
Vest4		0.78
MutPred		0.44		Loss of helix (P = 0.0093)
MVP		0.43
MPC		0.95
ClinPred		0.86	D
GERP RS		3.4
Varity_R		0.44
gMVP		0.36
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0099
dbscSNV1_RF	Benign	0.20
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

Other links and lift over

dbSNP: rs142662907; hg19: chr3-184019325;