1-35631342-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB2	NM_002794.5	c.217T>C	p.Tyr73His	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000373237.4	NP_002785.1
PSMB2	NM_001199779.2	c.142T>C	p.Tyr48His	missense_variant, splice_region_variant	Exon 3 of 6		NP_001186708.1
PSMB2	NM_001199780.2	c.-135T>C		splice_region_variant	Exon 2 of 5		NP_001186709.1
PSMB2	NM_001199780.2	c.-135T>C		5_prime_UTR_variant	Exon 2 of 5		NP_001186709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB2	ENST00000373237.4	c.217T>C	p.Tyr73His	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_002794.5	ENSP00000362334.3
PSMB2	ENST00000621781.4	c.-135T>C		splice_region_variant	Exon 2 of 5	1		ENSP00000479706.1
PSMB2	ENST00000621781.4	c.-135T>C		5_prime_UTR_variant	Exon 2 of 5	1		ENSP00000479706.1
PSMB2	ENST00000630477.1	n.105T>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.217T>C (p.Y73H) alteration is located in exon 3 (coding exon 3) of the PSMB2 gene. This alteration results from a T to C substitution at nucleotide position 217, causing the tyrosine (Y) at amino acid position 73 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
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
Varity_R		0.73
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-36096943;