Genetic Variant ZSWIM2:p.His352Arg (chr2-186829767-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_182521.3(ZSWIM2):c.1055A>G(p.His352Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ZSWIM2
NM_182521.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.63

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0330351).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182521.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZSWIM2	NM_182521.3	MANE Select	c.1055A>G	p.His352Arg	missense	Exon 8 of 9	NP_872327.2	Q8NEG5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZSWIM2	ENST00000295131.3	TSL:1 MANE Select	c.1055A>G	p.His352Arg	missense	Exon 8 of 9	ENSP00000295131.2	Q8NEG5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250768

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000411

AC:

AN:

1461286

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33436

American (AMR)

AF:

0.00

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111700

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.14

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.0023

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0060

LIST_S2

Benign

0.46

M_CAP

Benign

0.0038

MetaRNN

Benign

0.033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.26

PhyloP100

-1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.81

REVEL

Benign

0.029

Sift

Benign

0.57

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.093

MutPred

0.44

Gain of MoRF binding (P = 0.0542)

MVP

0.014

MPC

0.0099

ClinPred

0.019

GERP RS

-6.2

Varity_R

0.047

gMVP

0.21

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over