2-186828165-G-A

Variant summary

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

The NM_182521.3(ZSWIM2):​c.1721C>T​(p.Pro574Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,396 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZSWIM2
NM_182521.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.56
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]

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=0.091805965).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZSWIM2NM_182521.3 linkc.1721C>T p.Pro574Leu missense_variant Exon 9 of 9 ENST00000295131.3 NP_872327.2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZSWIM2ENST00000295131.3 linkc.1721C>T p.Pro574Leu missense_variant Exon 9 of 9 1 NM_182521.3 ENSP00000295131.2 Q8NEG5

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
152022
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000240
AC:
6
AN:
250334
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135298
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000272
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461374
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726982
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
152022
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 18, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1721C>T (p.P574L) alteration is located in exon 9 (coding exon 9) of the ZSWIM2 gene. This alteration results from a C to T substitution at nucleotide position 1721, causing the proline (P) at amino acid position 574 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
0.093
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
16
DANN
Benign
0.84
DEOGEN2
Benign
0.0056
T
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.24
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.41
T
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.092
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
1.4
L
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.032
Sift
Benign
0.15
T
Sift4G
Uncertain
0.013
D
Polyphen
0.42
B
Vest4
0.23
MutPred
0.23
Loss of disorder (P = 0.0605);
MVP
0.081
MPC
0.011
ClinPred
0.070
T
GERP RS
3.6
Varity_R
0.051
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.

Other links and lift over

dbSNP: rs761350596; hg19: chr2-187692892; COSMIC: COSV54575051; API