dbSNP rs372659616: NKD2:p.Pro99Gln (chr5-1033465-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033120.4(NKD2):c.296C>A(p.Pro99Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P99L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

NKD2
NM_033120.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.342

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18361771).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033120.4. 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
	NKD2	NM_033120.4	MANE Select	c.296C>A	p.Pro99Gln	missense	Exon 5 of 10	NP_149111.1	Q969F2-1
	NKD2	NM_001271082.2		c.296C>A	p.Pro99Gln	missense	Exon 5 of 11	NP_001258011.1	Q969F2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NKD2	ENST00000296849.10	TSL:1 MANE Select	c.296C>A	p.Pro99Gln	missense	Exon 5 of 10	ENSP00000296849.5	Q969F2-1
NKD2	ENST00000274150.4	TSL:1	c.296C>A	p.Pro99Gln	missense	Exon 5 of 11	ENSP00000274150.4	Q969F2-2
NKD2	ENST00000866687.1		c.296C>A	p.Pro99Gln	missense	Exon 6 of 11	ENSP00000536746.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693268

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31736

American (AMR)

AF:

0.00

AC:

AN:

36742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25240

East Asian (EAS)

AF:

0.00

AC:

AN:

35938

South Asian (SAS)

AF:

0.00

AC:

AN:

79664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082532

Other (OTH)

AF:

0.00

AC:

AN:

58194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.7

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.61

M_CAP

Benign

0.0051

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

PhyloP100

-0.34

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-2.3

REVEL

Benign

0.079

Sift

Benign

0.11

Sift4G

Benign

0.49

Polyphen

0.96

Vest4

0.24

MutPred

0.32

Loss of catalytic residue at P99 (P = 0.0353)

MVP

0.42

MPC

0.23

ClinPred

0.49

GERP RS

-0.87

Varity_R

0.051

gMVP

0.40

Mutation Taster

=84/16

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over