chr21-44115724-A-C

Position:

• chr21-44115724-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005049.3(PWP2):​c.640A>C​(p.Met214Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: PWP2 NM_005049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13742763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PWP2	NM_005049.3	c.640A>C	p.Met214Leu	missense_variant	7/21	ENST00000291576.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PWP2	ENST00000291576.12	c.640A>C	p.Met214Leu	missense_variant	7/21	1	NM_005049.3	P1
PWP2	ENST00000456705.1	c.540A>C	p.Ala180=	synonymous_variant	6/6	3
PWP2	ENST00000486126.1	n.363A>C		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.640A>C (p.M214L) alteration is located in exon 7 (coding exon 7) of the PWP2 gene. This alteration results from a A to C substitution at nucleotide position 640, causing the methionine (M) at amino acid position 214 to be replaced by a leucine (L). 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	0.090
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	16
DANN	Benign	0.59
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.041
Sift	Benign	0.37	T
Sift4G	Benign	0.53	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.53		Loss of phosphorylation at T219 (P = 0.2077);
MVP		0.26
MPC		0.15
ClinPred		0.084	T
GERP RS		2.3
Varity_R		0.030
gMVP		0.47

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: rs144385075; hg19: chr21-45535605;