5-1009502-C-T

Variant summary

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

The NM_033120.4(NKD2):​c.83C>T​(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,498,278 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 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

NKD2
NM_033120.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.391
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]

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=0.1742804).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NKD2NM_033120.4 linkc.83C>T p.Ala28Val missense_variant Exon 3 of 10 ENST00000296849.10 NP_149111.1 Q969F2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NKD2ENST00000296849.10 linkc.83C>T p.Ala28Val missense_variant Exon 3 of 10 1 NM_033120.4 ENSP00000296849.5 Q969F2-1
NKD2ENST00000274150.4 linkc.83C>T p.Ala28Val missense_variant Exon 3 of 11 1 ENSP00000274150.4 Q969F2-2

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
151978
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000417
AC:
4
AN:
95888
Hom.:
0
AF XY:
0.0000555
AC XY:
3
AN XY:
54022
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000521
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000832
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000267
AC:
36
AN:
1346192
Hom.:
0
Cov.:
31
AF XY:
0.0000301
AC XY:
20
AN XY:
664116
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000325
Gnomad4 ASJ exome
AF:
0.0000420
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000291
Gnomad4 OTH exome
AF:
0.0000536
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152086
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000416

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 21, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.83C>T (p.A28V) alteration is located in exon 3 (coding exon 3) of the NKD2 gene. This alteration results from a C to T substitution at nucleotide position 83, causing the alanine (A) at amino acid position 28 to be replaced by a valine (V). 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
0.15
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;.
Eigen
Benign
-0.57
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.034
N
LIST_S2
Benign
0.50
T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.2
L;L
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-2.2
N;N
REVEL
Benign
0.042
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.058
T;T
Polyphen
1.0
D;D
Vest4
0.20
MVP
0.21
MPC
0.23
ClinPred
0.25
T
GERP RS
0.70
Varity_R
0.088
gMVP
0.33

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: rs1381562356; hg19: chr5-1009617; COSMIC: COSV56892102; COSMIC: COSV56892102; API