14-24145152-T-G

Position:

• chr14-24145152-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002818.3(PSME2):​c.266A>C​(p.His89Pro) variant causes a missense change. The variant allele was found at a frequency of 0.993 in 152,252 control chromosomes in the GnomAD database, including 75,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.99 (75098 hom., cov: 30)
  • Exomes 𝑓: 0.99 (716676 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSME2 NM_002818.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.34

Genes affected

PSME2 (HGNC:9569): (proteasome activator subunit 2) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core 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. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase 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. The immunoproteasome contains an alternate regulator, referred to as the 11S regulator or PA28, that replaces the 19S regulator. Three subunits (alpha, beta and gamma) of the 11S regulator have been identified. This gene encodes the beta subunit of the 11S regulator, one of the two 11S subunits that is induced by gamma-interferon. Three beta and three alpha subunits combine to form a heterohexameric ring. Six pseudogenes have been identified on chromosomes 4, 5, 8, 10 and 13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.717483E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSME2	NM_002818.3	c.266A>C	p.His89Pro	missense_variant	6/11	ENST00000216802.10	NP_002809.2
PSME2	XM_006720213.3	c.35A>C	p.His12Pro	missense_variant	6/11		XP_006720276.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSME2	ENST00000216802.10	c.266A>C	p.His89Pro	missense_variant	6/11	1	NM_002818.3	ENSP00000216802	P1

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151101 AN: 152134 Hom.: 75039 Cov.: 30

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.991

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.990

Gnomad OTH AF: 0.989

GnomAD3 exomes AF: 0.993 AC: 249365 AN: 251182 Hom.: 123787 AF XY: 0.992 AC XY: 134709 AN XY: 135744

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 0.988

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.997

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.989

Gnomad OTH exome AF: 0.992

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.990 AC: 1447145 AN: 1461128 Hom.: 716676 Cov.: 56 AF XY: 0.990 AC XY: 719981 AN XY: 726952

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.994

Gnomad4 ASJ exome AF: 0.989

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 0.998

Gnomad4 NFE exome AF: 0.989

Gnomad4 OTH exome AF: 0.992

GnomAD4 genome AF: 0.993 AC: 151219 AN: 152252 Hom.: 75098 Cov.: 30 AF XY: 0.994 AC XY: 73962 AN XY: 74438

Gnomad4 AFR AF: 0.998

Gnomad4 AMR AF: 0.991

Gnomad4 ASJ AF: 0.989

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.998

Gnomad4 FIN AF: 0.998

Gnomad4 NFE AF: 0.990

Gnomad4 OTH AF: 0.989

Alfa AF: 0.990 Hom.: 135492

Bravo AF: 0.993

TwinsUK AF: 0.990 AC: 3672

ALSPAC AF: 0.988 AC: 3806

ESP6500AA AF: 0.998 AC: 4398

ESP6500EA AF: 0.989 AC: 8507

ExAC AF: 0.993 AC: 120548

Asia WGS AF: 0.999 AC: 3475 AN: 3478

EpiCase AF: 0.990

EpiControl AF: 0.989

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.025
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Benign	0.83
DEOGEN2	Benign	0.0073	T;.;T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.031	N
MetaRNN	Benign	5.7e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-3.0	.;.;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	3.2	N;.;N;N
REVEL	Benign	0.091
Sift	Benign	0.68	T;.;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.17
MPC		0.85
ClinPred		0.0054	T
GERP RS		4.4
Varity_R		0.083
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7146672; hg19: chr14-24614361;