Genetic Variant ZSWIM2:p.Tyr390Cys (chr2-186828717-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_182521.3(ZSWIM2):c.1169A>G(p.Tyr390Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,611,240 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 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

ZSWIM2
NM_182521.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

Variant links:

Genes affected

ZSWIM2 (HGNC:30990): (zinc finger SWIM-type containing 2) Predicted to enable ubiquitin-protein transferase activity. Predicted to be involved in apoptotic process and protein polyubiquitination. Predicted to act upstream of or within positive regulation of extrinsic apoptotic signaling pathway via death domain receptors. [provided by Alliance of Genome Resources, Apr 2022]

ZSWIM2 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=0.07627568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM2	NM_182521.3 link	c.1169A>G	p.Tyr390Cys	missense_variant	Exon 9 of 9	ENST00000295131.3	NP_872327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSWIM2	ENST00000295131.3 link	c.1169A>G	p.Tyr390Cys	missense_variant	Exon 9 of 9	1	NM_182521.3	ENSP00000295131.2		Q8NEG5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000644

AC:

AN:

248506

Hom.:

AF XY:

0.0000521

AC XY:

AN XY:

134384

show subpopulations

Gnomad AFR exome

AF:

0.000866

Gnomad AMR exome

AF:

0.0000589

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1459152

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725750

show subpopulations

Gnomad4 AFR exome

AF:

0.000629

Gnomad4 AMR exome

AF:

0.0000452

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000210

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.000724

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000507

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000742

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1169A>G (p.Y390C) alteration is located in exon 9 (coding exon 9) of the ZSWIM2 gene. This alteration results from a A to G substitution at nucleotide position 1169, causing the tyrosine (Y) at amino acid position 390 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

0.14

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.045

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.024

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.74

M_CAP

Benign

0.023

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.17

Sift

Benign

0.077

Sift4G

Uncertain

0.0020

Polyphen

0.062

Vest4

0.40

MVP

0.27

MPC

0.011

ClinPred

0.039

GERP RS

4.0

Varity_R

0.14

gMVP

0.57

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