Genetic Variant CWC22:p.Lys893Glu (chr2-179945179-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020943.3(CWC22):c.2677A>G(p.Lys893Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

CWC22
NM_020943.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

Variant links:

Genes affected

CWC22 (HGNC:29322): (CWC22 spliceosome associated protein homolog) Enables RNA binding activity. Involved in mRNA splicing, via spliceosome. Located in cytosol and nuclear speck. Part of U2-type catalytic step 1 spliceosome; U2-type catalytic step 2 spliceosome; and U2-type precatalytic spliceosome. [provided by Alliance of Genome Resources, Apr 2022]

CWC22 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07109493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CWC22	NM_020943.3 link	c.2677A>G	p.Lys893Glu	missense_variant	Exon 20 of 20	ENST00000410053.8	NP_065994.1	Q9HCG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CWC22	ENST00000410053.8 link	c.2677A>G	p.Lys893Glu	missense_variant	Exon 20 of 20	1	NM_020943.3	ENSP00000387006.3		Q9HCG8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2677A>G (p.K893E) alteration is located in exon 20 (coding exon 19) of the CWC22 gene. This alteration results from a A to G substitution at nucleotide position 2677, causing the lysine (K) at amino acid position 893 to be replaced by a glutamic acid (E). 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

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.021

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.55

M_CAP

Benign

0.0048

MetaRNN

Benign

0.071

MetaSVM

Benign

-0.98

MutationAssessor

Benign

2.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.040

REVEL

Benign

0.027

Sift

Uncertain

0.0050

Sift4G

Benign

0.41

Polyphen

0.39

Vest4

0.13

MutPred

0.23

Loss of methylation at K893 (P = 0.0206);

MVP

0.19

MPC

0.15

ClinPred

0.44

GERP RS

4.9

Varity_R

0.095

gMVP

0.071

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over