rs2071543

Positions:

• chr6-32843852-G-C
• chr6-32843852-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_148919.4(PSMB8):​c.145C>G​(p.Gln49Glu) 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. 14/23 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. Q49K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSMB8 NM_148919.4 missense, splice_region
• Scores: Splicing: ADA: 0.9306
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.24

Genes affected

PSMB8 (HGNC:9545): (proteasome 20S subunit beta 8) 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. This gene is located in the class II region of the MHC (major histocompatibility complex). Expression of this gene is induced by gamma interferon and this gene product replaces catalytic subunit 3 (proteasome beta 5 subunit) in the immunoproteasome. Proteolytic processing is required to generate a mature subunit. Two alternative transcripts encoding two isoforms have been identified; both isoforms are processed to yield the same mature subunit. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20460635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.145C>G	p.Gln49Glu	missense_variant, splice_region_variant	1/6	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5	c.135+427C>G		intron_variant			NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8	c.145C>G	p.Gln49Glu	missense_variant, splice_region_variant	1/6	1	NM_148919.4	ENSP00000364016	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.0090	T;T
Eigen	Benign	-0.017
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.53	N;N
REVEL	Benign	0.070
Sift	Benign	0.54	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	.;B
Vest4		0.37
MutPred		0.21		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.68
MPC		0.60
ClinPred		0.68	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.93
dbscSNV1_RF	Benign	0.65
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2071543; hg19: chr6-32811629;