Variant 3-28478878-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_001040432.4(ZCWPW2):c.557A>G(p.Tyr186Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,590,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ZCWPW2
NM_001040432.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.326

Variant links:

Genes affected

ZCWPW2 (HGNC:23574): (zinc finger CW-type and PWWP domain containing 2) Enables methylated histone binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZCWPW2 links:

Genome browser will be placed here

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=0.08734584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ZCWPW2	NM_001040432.4 linkuse as main transcript	c.557A>G	p.Tyr186Cys	missense_variant	5/10	ENST00000383768.7	NP_001035522.1
ZCWPW2	NM_001324169.2 linkuse as main transcript	c.557A>G	p.Tyr186Cys	missense_variant	4/9		NP_001311098.1
ZCWPW2	NM_001324170.2 linkuse as main transcript	c.493-13249A>G		intron_variant			NP_001311099.1
ZCWPW2	NR_136708.2 linkuse as main transcript	n.989-13249A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZCWPW2	ENST00000383768.7 linkuse as main transcript	c.557A>G	p.Tyr186Cys	missense_variant	5/10	1	NM_001040432.4	ENSP00000373278	P1
ZCWPW2	ENST00000419130.5 linkuse as main transcript	c.212A>G	p.Tyr71Cys	missense_variant	3/8	1		ENSP00000395687

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000344

AC:

AN:

232696

Hom.:

AF XY:

0.0000316

AC XY:

AN XY:

126526

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1438226

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

714818

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000126

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2022

The c.557A>G (p.Y186C) alteration is located in exon 4 (coding exon 3) of the ZCWPW2 gene. This alteration results from a A to G substitution at nucleotide position 557, causing the tyrosine (Y) at amino acid position 186 to be replaced by a cysteine (C). 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

0.088

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.011

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.71

M_CAP

Benign

0.011

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

MutationTaster

Benign

0.83

N;N

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.040

Sift

Uncertain

0.0060

Sift4G

Pathogenic

0.0

Polyphen

0.044

Vest4

0.23

MutPred

0.37

Gain of helix (P = 0.0128);

MVP

0.18

MPC

0.093

ClinPred

0.32

GERP RS

2.5

Varity_R

0.12

gMVP

0.14

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