chr1-35605265-C-A

Variant names:

• chr1-35605265-C-A
• NM_002794.5:c.466G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002794.5(PSMB2):​c.466G>T​(p.Ala156Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A156T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSMB2 NM_002794.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB2	NM_002794.5	c.466G>T	p.Ala156Ser	missense_variant	Exon 5 of 6	ENST00000373237.4	NP_002785.1
PSMB2	NM_001199779.2	c.391G>T	p.Ala131Ser	missense_variant	Exon 5 of 6		NP_001186708.1
PSMB2	NM_001199780.2	c.115G>T	p.Ala39Ser	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.466G>T	p.Ala156Ser	missense_variant	Exon 5 of 6	1	NM_002794.5	ENSP00000362334.3
PSMB2	ENST00000621781.4	c.115G>T	p.Ala39Ser	missense_variant	Exon 4 of 5	1		ENSP00000479706.1
PSMB2	ENST00000630477.1	n.354G>T		non_coding_transcript_exon_variant	Exon 4 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460810 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726758

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.049	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.0	.;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	.;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.010	.;D
Sift4G	Uncertain	0.017	D;D
Polyphen		0.99	.;D
Vest4		0.65
MutPred		0.78		.;Gain of phosphorylation at A156 (P = 0.013);
MVP		0.43
MPC		1.6
ClinPred		0.98	D
GERP RS		6.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.50
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-36070866;