rs2071627

Variant names:

• chr6-32841446-C-A
• rs2071627
• NM_148919.4:c.742+85G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-32841446-C-A
• chr6-32841446-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_148919.4(PSMB8):​c.742+85G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.395 in 1,392,178 control chromosomes in the GnomAD database, including 111,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10304 hom., cov: 32)
  • Exomes 𝑓: 0.40 (101164 hom.)
• Consequence: PSMB8 NM_148919.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0200
• Publications: 8 publications found

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]

PSMB8 Gene-Disease associations (from GenCC):

• proteasome-associated autoinflammatory syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• proteosome-associated autoinflammatory syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-32841446-C-A is Benign according to our data. Variant chr6-32841446-C-A is described in ClinVar as Benign. ClinVar VariationId is 1239292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSMB8	NM_148919.4	c.742+85G>T		intron_variant	Intron 5 of 5	ENST00000374882.8	NP_683720.2
PSMB8	NM_004159.5	c.730+85G>T		intron_variant	Intron 5 of 5		NP_004150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSMB8	ENST00000374882.8	c.742+85G>T		intron_variant	Intron 5 of 5	1	NM_148919.4	ENSP00000364016.4

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55164 AN: 151916 Hom.: 10309 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.478

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.352

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.415

Gnomad OTH AF: 0.372

GnomAD4 exome AF: 0.399 AC: 494656 AN: 1240144 Hom.: 101164 AF XY: 0.398 AC XY: 249768 AN XY: 627534

African (AFR) AF: 0.306 AC: 8846 AN: 28892

American (AMR) AF: 0.300 AC: 13271 AN: 44232

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 8501 AN: 24842

East Asian (EAS) AF: 0.250 AC: 9672 AN: 38636

South Asian (SAS) AF: 0.333 AC: 27235 AN: 81752

European-Finnish (FIN) AF: 0.378 AC: 19008 AN: 50254

Middle Eastern (MID) AF: 0.480 AC: 1784 AN: 3718

European-Non Finnish (NFE) AF: 0.421 AC: 385421 AN: 914892

Other (OTH) AF: 0.395 AC: 20918 AN: 52926

GnomAD4 genome AF: 0.363 AC: 55156 AN: 152034 Hom.: 10304 Cov.: 32 AF XY: 0.358 AC XY: 26599 AN XY: 74326

African (AFR) AF: 0.304 AC: 12621 AN: 41452

American (AMR) AF: 0.323 AC: 4942 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1137 AN: 3472

East Asian (EAS) AF: 0.231 AC: 1193 AN: 5174

South Asian (SAS) AF: 0.350 AC: 1686 AN: 4822

European-Finnish (FIN) AF: 0.381 AC: 4025 AN: 10564

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.415 AC: 28197 AN: 67942

Other (OTH) AF: 0.368 AC: 777 AN: 2114

Alfa AF: 0.240 Hom.: 564

Bravo AF: 0.355

Asia WGS AF: 0.273 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Nov 14, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 46% of patients studied by a panel of primary immunodeficiencies. Number of patients: 44. Only high quality variants are reported. -

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.79
PhyloP100		0.020
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2071627; hg19: chr6-32809223;