17-28043061-C-G

Variant summary

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

The NM_016231.5(NLK):​c.188C>G​(p.Pro63Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NLK
NM_016231.5 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.25
Variant links:
Genes affected
NLK (HGNC:29858): (nemo like kinase) Enables ubiquitin protein ligase binding activity. Involved in protein stabilization and transforming growth factor beta receptor signaling pathway. Predicted to be located in cytosol and nucleoplasm. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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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=0.14570114).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NLKNM_016231.5 linkuse as main transcriptc.188C>G p.Pro63Arg missense_variant 1/11 ENST00000407008.8 NP_057315.3 Q9UBE8A0A024QZ12
NLKXM_005257988.3 linkuse as main transcriptc.188C>G p.Pro63Arg missense_variant 1/10 XP_005258045.1
NLKXR_001752526.3 linkuse as main transcriptn.385C>G non_coding_transcript_exon_variant 1/9
NLKXR_934482.2 linkuse as main transcriptn.385C>G non_coding_transcript_exon_variant 1/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NLKENST00000407008.8 linkuse as main transcriptc.188C>G p.Pro63Arg missense_variant 1/111 NM_016231.5 ENSP00000384625.3 Q9UBE8
NLKENST00000582037.2 linkuse as main transcriptc.188C>G p.Pro63Arg missense_variant 1/22 ENSP00000464656.1 J3QSE9
NLKENST00000496808.1 linkuse as main transcriptn.32C>G non_coding_transcript_exon_variant 1/122 ENSP00000433117.1 H0YD75
NLKENST00000583517.1 linkuse as main transcriptn.44-27C>G intron_variant 3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 01, 2021The c.188C>G (p.P63R) alteration is located in exon 1 (coding exon 1) of the NLK gene. This alteration results from a C to G substitution at nucleotide position 188, causing the proline (P) at amino acid position 63 to be replaced by an arginine (R). 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
0.23
BayesDel_addAF
Benign
-0.058
T
BayesDel_noAF
Benign
-0.32
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Benign
0.40
T;.
Eigen
Benign
-0.14
Eigen_PC
Benign
0.080
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.34
N;.
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.51
N;.
REVEL
Benign
0.063
Sift
Uncertain
0.0020
D;.
Sift4G
Benign
0.86
T;T
Polyphen
0.037
B;.
Vest4
0.23
MutPred
0.35
Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);
MVP
0.41
MPC
1.2
ClinPred
0.69
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.22
gMVP
0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-26370087; API