NM_002794.5:c.217T>C

Variant names:

• chr1-35631342-A-G
• NM_002794.5:c.217T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002794.5(PSMB2):​c.217T>C​(p.Tyr73His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMB2 NM_002794.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.96
• Publications: 0 publications found

Genes affected

PSMB2 (HGNC:9539): (proteasome 20S subunit beta 2) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure 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. 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 a member of the proteasome B-type family, also known as the T1B family, that is a 20S core beta subunit. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002794.5. 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
	PSMB2	NM_002794.5	MANE Select	c.217T>C	p.Tyr73His	missense splice_region	Exon 3 of 6	NP_002785.1	P49721
	PSMB2	NM_001199779.2		c.142T>C	p.Tyr48His	missense splice_region	Exon 3 of 6	NP_001186708.1	B7Z478
	PSMB2	NM_001199780.2		c.-135T>C		splice_region	Exon 2 of 5	NP_001186709.1	A0A087WVV1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMB2	ENST00000373237.4	TSL:1 MANE Select	c.217T>C	p.Tyr73His	missense splice_region	Exon 3 of 6	ENSP00000362334.3	P49721
	PSMB2	ENST00000621781.4	TSL:1	c.-135T>C		splice_region	Exon 2 of 5	ENSP00000479706.1	A0A087WVV1
	PSMB2	ENST00000621781.4	TSL:1	c.-135T>C		5_prime_UTR	Exon 2 of 5	ENSP00000479706.1	A0A087WVV1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.028	D
Sift4G	Benign	0.10	T
Polyphen		0.29	B
Vest4		0.79
MutPred		0.45		Gain of disorder (P = 0.0218)
MVP		0.52
MPC		1.5
ClinPred		0.98	D
GERP RS		5.5
PromoterAI		-0.024	Neutral
Varity_R		0.73
gMVP		0.83
Mutation Taster		=27/73	disease causing

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

Other links and lift over

hg19: chr1-36096943;