rs2304974

Positions:

• chr17-4797698-C-G
• chr17-4797698-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000270586.8(PSMB6):​c.319C>G​(p.Pro107Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,614,050 control chromosomes in the GnomAD database, including 531 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (56 hom., cov: 32)
  • Exomes 𝑓: 0.016 (475 hom.)
• Consequence: PSMB6 ENST00000270586.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89

Genes affected

PSMB6 (HGNC:9543): (proteasome 20S subunit beta 6) 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. The encoded protein is a member of the proteasome B-type family, also known as the T1B family, and is a 20S core beta subunit in the proteasome. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017100871).
• BP6: Variant 17-4797698-C-G is Benign according to our data. Variant chr17-4797698-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMB6	NM_002798.3	c.319C>G	p.Pro107Ala	missense_variant	4/6	ENST00000270586.8	NP_002789.1
PSMB6	NM_001270481.2	c.319C>G	p.Pro107Ala	missense_variant	4/6		NP_001257410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMB6	ENST00000270586.8	c.319C>G	p.Pro107Ala	missense_variant	4/6	1	NM_002798.3	ENSP00000270586	P1
PSMB6	ENST00000614486.4	c.319C>G	p.Pro107Ala	missense_variant	4/6	2		ENSP00000485006
PSMB6	ENST00000575643.1	n.15C>G		non_coding_transcript_exon_variant	1/2	2
PSMB6	ENST00000571309.1	c.294-19C>G		intron_variant, NMD_transcript_variant		3		ENSP00000460811

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2170 AN: 152072 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00348

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.0469

Gnomad FIN AF: 0.00906

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00923

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0257 AC: 6468 AN: 251338 Hom.: 195 AF XY: 0.0250 AC XY: 3401 AN XY: 135838

Gnomad AFR exome AF: 0.00338

Gnomad AMR exome AF: 0.0453

Gnomad ASJ exome AF: 0.00636

Gnomad EAS exome AF: 0.107

Gnomad SAS exome AF: 0.0466

Gnomad FIN exome AF: 0.00795

Gnomad NFE exome AF: 0.00976

Gnomad OTH exome AF: 0.0178

GnomAD4 exome AF: 0.0162 AC: 23626 AN: 1461860 Hom.: 475 Cov.: 32 AF XY: 0.0167 AC XY: 12161 AN XY: 727236

Gnomad4 AFR exome AF: 0.00218

Gnomad4 AMR exome AF: 0.0433

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.0450

Gnomad4 FIN exome AF: 0.00841

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0142 AC: 2168 AN: 152190 Hom.: 56 Cov.: 32 AF XY: 0.0152 AC XY: 1129 AN XY: 74398

Gnomad4 AFR AF: 0.00347

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0467

Gnomad4 FIN AF: 0.00906

Gnomad4 NFE AF: 0.00923

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0116 Hom.: 34

Bravo AF: 0.0147

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0113 AC: 97

ExAC AF: 0.0238 AC: 2889

Asia WGS AF: 0.0850 AC: 295 AN: 3478

EpiCase AF: 0.00965

EpiControl AF: 0.00806

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	0.010
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L
MutationTaster	Benign	0.0050	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.3	.;N
REVEL	Benign	0.071
Sift	Benign	0.13	.;T
Sift4G	Benign	0.20	T;T
Polyphen		0.0	.;B
Vest4		0.13
MPC		0.49
ClinPred		0.017	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs2304974; hg19: chr17-4700993; COSMIC: COSV99566930; COSMIC: COSV99566930;