17-28043059-C-G

Variant names:

• chr17-28043059-C-G
• rs1908919566
• NM_016231.5:c.186C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016231.5(NLK):​c.186C>G​(p.His62Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
• Consequence: NLK NM_016231.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.318532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NLK	NM_016231.5	c.186C>G	p.His62Gln	missense_variant	Exon 1 of 11	ENST00000407008.8	NP_057315.3
NLK	XM_005257988.3	c.186C>G	p.His62Gln	missense_variant	Exon 1 of 10		XP_005258045.1
NLK	XR_001752526.3	n.383C>G		non_coding_transcript_exon_variant	Exon 1 of 9
NLK	XR_934482.2	n.383C>G		non_coding_transcript_exon_variant	Exon 1 of 12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NLK	ENST00000407008.8	c.186C>G	p.His62Gln	missense_variant	Exon 1 of 11	1	NM_016231.5	ENSP00000384625.3
NLK	ENST00000582037.2	c.186C>G	p.His62Gln	missense_variant	Exon 1 of 2	2		ENSP00000464656.1
NLK	ENST00000496808.1	n.30C>G		non_coding_transcript_exon_variant	Exon 1 of 12	2		ENSP00000433117.1
NLK	ENST00000583517.1	n.44-29C>G		intron_variant	Intron 1 of 2	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

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.186C>G (p.H62Q) 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 186, causing the histidine (H) at amino acid position 62 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.98	N;.
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D;.
Sift4G	Benign	0.42	T;T
Polyphen		0.46	P;.
Vest4		0.42
MutPred		0.20		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.71
MPC		1.0
ClinPred		0.63	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1908919566; hg19: chr17-26370085;