rs2020945

chr21-44109038-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005049.3(PWP2):c.73G>A(p.Asp25Asn) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D25G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 9)
• Consequence: PWP2 NM_005049.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

Genes affected

PWP2 (HGNC:9711): (PWP2 small subunit processome component) Enables RNA binding activity. Predicted to be involved in maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) and ribosomal small subunit assembly. Predicted to be located in nucleoplasm. Predicted to be part of Pwp2p-containing subcomplex of 90S preribosome and small-subunit processome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3400784E-4).
• BS2: High AC in GnomAdExome at 181913 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PWP2	NM_005049.3	c.73G>A	p.Asp25Asn	missense_variant	2/21	ENST00000291576.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PWP2	ENST00000291576.12	c.73G>A	p.Asp25Asn	missense_variant	2/21	1	NM_005049.3	P1
PWP2	ENST00000456705.1	c.73G>A	p.Asp25Asn	missense_variant	2/6	3

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD3 exomes AF: 0.724 AC: 181913 AN: 251288 Hom.: 68303 AF XY: 0.729 AC XY: 98984 AN XY: 135830

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.677

Gnomad ASJ exome AF: 0.743

Gnomad EAS exome AF: 0.706

Gnomad SAS exome AF: 0.580

Gnomad FIN exome AF: 0.844

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.757

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 9

Alfa AF: 0.777 Hom.: 95951

TwinsUK AF: 0.800 AC: 2968

ALSPAC AF: 0.805 AC: 3101

ESP6500AA AF: 0.323 AC: 1425

ESP6500EA AF: 0.808 AC: 6948

ExAC AF: 0.715 AC: 86839

Asia WGS AF: 0.603 AC: 2100 AN: 3478

EpiCase AF: 0.815

EpiControl AF: 0.811

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	0.016
Eigen_PC	Benign	0.044
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;D
MetaRNN	Benign	0.00023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	0.00054	P
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Benign	0.23
Sift	Benign	0.074	T;D
Sift4G	Uncertain	0.056	T;T
Polyphen		0.70	P;.
Vest4		0.28
MPC		0.22
ClinPred		0.095	T
GERP RS		3.9
Varity_R		0.32
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: rs2020945; hg19: chr21-45528919; COSMIC: COSV52378282; COSMIC: COSV52378282;