Genetic Variant NKD2:p.Pro99Leu (chr5-1033465-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033120.4(NKD2):c.296C>T(p.Pro99Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000964 in 1,556,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

NKD2
NM_033120.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.342

Variant links:

Genes affected

NKD2 (HGNC:17046): (NKD inhibitor of WNT signaling pathway 2) This gene encodes a member of a family of proteins that function as negative regulators of Wnt receptor signaling through interaction with Dishevelled family members. The encoded protein participates in the delivery of transforming growth factor alpha-containing vesicles to the cell membrane. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]

NKD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06557199).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKD2	NM_033120.4 link	c.296C>T	p.Pro99Leu	missense_variant	Exon 5 of 10	ENST00000296849.10	NP_149111.1	Q969F2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKD2	ENST00000296849.10 link	c.296C>T	p.Pro99Leu	missense_variant	Exon 5 of 10	1	NM_033120.4	ENSP00000296849.5		Q969F2-1
NKD2	ENST00000274150.4 link	c.296C>T	p.Pro99Leu	missense_variant	Exon 5 of 11	1		ENSP00000274150.4		Q969F2-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000374

AC:

AN:

160556

Hom.:

AF XY:

0.0000352

AC XY:

AN XY:

85264

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000392

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000860

Gnomad SAS exome

AF:

0.0000433

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000479

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000997

AC:

AN:

1404014

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

693268

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000544

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000557

Gnomad4 SAS exome

AF:

0.0000251

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000739

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.0000497

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000268

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.296C>T (p.P99L) alteration is located in exon 5 (coding exon 5) of the NKD2 gene. This alteration results from a C to T substitution at nucleotide position 296, causing the proline (P) at amino acid position 99 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

0.071

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0025

MetaRNN

Benign

0.066

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.7

D;D

REVEL

Benign

0.027

Sift

Benign

0.12

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.022

B;B

Vest4

0.14

MVP

0.20

MPC

0.044

ClinPred

0.032

GERP RS

-0.87

Varity_R

0.051

gMVP

0.43

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