NM_016231.5:c.208T>A

Variant names:

• chr17-28043081-T-A
• rs1908921385
• NM_016231.5:c.208T>A
• NLK p.Ser70Thr

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_016231.5(NLK):c.208T>A (p.Ser70Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000704 (AC=1) in the gnomAD database across 1,420,218 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000917. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NLK NM_016231.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29
• Publications: 0 publications found

Genes affected

NLK (HGNC:29858): (nemo like kinase) Enables DNA-binding transcription factor binding activity; protein serine/threonine kinase activity; and ubiquitin protein ligase binding activity. Involved in several processes, including negative regulation of TORC1 signaling; 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, Jul 2025]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000917 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_016231.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NLK NM_016231.5	MANE Select	c.208T>A p.Ser70Thr	missense	Exon 1 of 11	Prot: NP_057315.3

NLK NM_016231.5

MANE Select

HGVSc / HGVSpc.208T>Ap.Ser70Thr

Exon rankExon 1 of 11

missense

Prot: NP_057315.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NLK ENST00000407008.8	TSL:1MANE Select	c.208T>A p.Ser70Thr	missense	Exon 1 of 11	Prot: ENSP00000384625.3 UniProt:
	NLK ENST00000955373.1		c.208T>A p.Ser70Thr	missense	Exon 2 of 12	Prot: ENSP00000625432.1 UniProt:
	NLK ENST00000923558.1		c.208T>A p.Ser70Thr	missense	Exon 1 of 11	Prot: ENSP00000593617.1 UniProt:

NLK ENST00000407008.8

TSL:1MANE Select

HGVSc / HGVSpc.208T>Ap.Ser70Thr

Exon rankExon 1 of 11

missense

Prot: ENSP00000384625.3UniProt: Q9UBE8

NLK ENST00000955373.1

HGVSc / HGVSpc.208T>Ap.Ser70Thr

Exon rankExon 2 of 12

missense

Prot: ENSP00000625432.1UniProt: Q9UBE8

NLK ENST00000923558.1

HGVSc / HGVSpc.208T>Ap.Ser70Thr

Exon rankExon 1 of 11

missense

Prot: ENSP00000593617.1UniProt: A0ACI8T789

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 7.04e-7	AC:1	Hom:0	AN:1420218	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	63156	0.00000818	1	122294

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	23
DANN	Benign	0.91
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
FuncVEP CTI	Benign	0.0086
GPN-Star LLR	N/A	-8.2
GPN-Star score	N/A	8.2
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.0	N
PhyloP100	Uncertain	5.3
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.65	T
PromoterAI	N/A	-0.045	Neutral
PROVEAN	Benign	0.0	N
REVEL	Benign	0.092
Sift	Benign	0.17	T
Sift4G	Benign	0.59	T
Varity_R	N/A	0.12
VESM-3B	Benign	-3.1

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1908921385;

hg19: chr17-26370107;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar