chr1-35603305-C-T

Variant names:

• chr1-35603305-C-T
• NM_002794.5:c.568G>A

Variant summary

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

The NM_002794.5(PSMB2):​c.568G>A​(p.Asp190Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PSMB2 NM_002794.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1750269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB2	NM_002794.5	c.568G>A	p.Asp190Asn	missense_variant	Exon 6 of 6	ENST00000373237.4	NP_002785.1
PSMB2	NM_001199779.2	c.493G>A	p.Asp165Asn	missense_variant	Exon 6 of 6		NP_001186708.1
PSMB2	NM_001199780.2	c.217G>A	p.Asp73Asn	missense_variant	Exon 5 of 5		NP_001186709.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB2	ENST00000373237.4	c.568G>A	p.Asp190Asn	missense_variant	Exon 6 of 6	1	NM_002794.5	ENSP00000362334.3
PSMB2	ENST00000621781.4	c.217G>A	p.Asp73Asn	missense_variant	Exon 5 of 5	1		ENSP00000479706.1
PSMB2	ENST00000630477.1	n.456G>A		non_coding_transcript_exon_variant	Exon 5 of 5	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461830 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727220

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: 0.0000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.568G>A (p.D190N) alteration is located in exon 6 (coding exon 6) of the PSMB2 gene. This alteration results from a G to A substitution at nucleotide position 568, causing the aspartic acid (D) at amino acid position 190 to be replaced by an asparagine (N). 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	0.11
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	.;T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	.;N
REVEL	Benign	0.071
Sift	Benign	0.27	.;T
Sift4G	Benign	0.065	T;T
Polyphen		0.0	.;B
Vest4		0.10
MutPred		0.39		.;Loss of helix (P = 0.079);
MVP		0.49
MPC		0.67
ClinPred		0.55	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.086
gMVP		0.64

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: chr1-36068906;