Genetic Variant NWD2:p.Thr192Ile (chr4-37433889-C-T) – 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_001144990.2(NWD2):c.575C>T(p.Thr192Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000431 in 1,392,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

NWD2
NM_001144990.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Publications

0 publications found

Variant links:

Genes affected

NWD2 (HGNC:29229): (NACHT and WD repeat domain containing 2)

NWD2 links:

Genome browser will be placed here

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=0.060047686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NWD2	NM_001144990.2 link	c.575C>T	p.Thr192Ile	missense_variant	Exon 5 of 7	ENST00000309447.6	NP_001138462.1	Q9ULI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NWD2	ENST00000309447.6 link	c.575C>T	p.Thr192Ile	missense_variant	Exon 5 of 7	5	NM_001144990.2	ENSP00000309501.5		Q9ULI1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000194

AC:

AN:

154282

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000431

AC:

AN:

1392414

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31434

American (AMR)

AF:

0.00

AC:

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24884

East Asian (EAS)

AF:

0.000168

AC:

AN:

35648

South Asian (SAS)

AF:

0.00

AC:

AN:

77852

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5664

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075026

Other (OTH)

AF:

0.00

AC:

AN:

57692

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.575C>T (p.T192I) alteration is located in exon 5 (coding exon 5) of the NWD2 gene. This alteration results from a C to T substitution at nucleotide position 575, causing the threonine (T) at amino acid position 192 to be replaced by an isoleucine (I). 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

0.079

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0077

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.48

M_CAP

Benign

0.030

MetaRNN

Benign

0.060

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.1

PhyloP100

2.0

PrimateAI

Benign

0.29

PROVEAN

Benign

0.62

REVEL

Benign

0.16

Sift

Benign

0.064

Sift4G

Uncertain

0.016

Polyphen

0.010

Vest4

0.060

MutPred

0.32

Gain of glycosylation at T192 (P = 0.0349);

MVP

0.088

ClinPred

0.053

GERP RS

0.37

Varity_R

0.063

gMVP

0.24

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over