chr1-35605246-T-G

Variant names:

• chr1-35605246-T-G
• NM_002794.5:c.485A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002794.5(PSMB2):​c.485A>C​(p.Lys162Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. K162E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSMB2 NM_002794.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88

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.485A>C	p.Lys162Thr	missense_variant	Exon 5 of 6	ENST00000373237.4	NP_002785.1
PSMB2	NM_001199779.2	c.410A>C	p.Lys137Thr	missense_variant	Exon 5 of 6		NP_001186708.1
PSMB2	NM_001199780.2	c.134A>C	p.Lys45Thr	missense_variant	Exon 4 of 5		NP_001186709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB2	ENST00000373237.4	c.485A>C	p.Lys162Thr	missense_variant	Exon 5 of 6	1	NM_002794.5	ENSP00000362334.3
PSMB2	ENST00000621781.4	c.134A>C	p.Lys45Thr	missense_variant	Exon 4 of 5	1		ENSP00000479706.1
PSMB2	ENST00000630477.1	n.373A>C		non_coding_transcript_exon_variant	Exon 4 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.485A>C (p.K162T) alteration is located in exon 5 (coding exon 5) of the PSMB2 gene. This alteration results from a A to C substitution at nucleotide position 485, causing the lysine (K) at amino acid position 162 to be replaced by a threonine (T). 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	Benign	0.22
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	.;D
REVEL	Benign	0.22
Sift	Benign	0.065	.;T
Sift4G	Benign	0.064	T;T
Polyphen		0.096	.;B
Vest4		0.80
MutPred		0.59		.;Loss of stability (P = 0.1476);
MVP		0.52
MPC		1.2
ClinPred		0.96	D
GERP RS		6.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.71
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: chr1-36070847;