rs199827465

chr4-169479405-C-Achr4-169479405-C-Gchr4-169479405-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199397.3(NEK1):c.2137G>T(p.Val713Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,455,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V713M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NEK1 NM_001199397.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002512
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.180

Genes affected

NEK1 (HGNC:7744): (NIMA related kinase 1) The protein encoded by this gene is a serine/threonine kinase involved in cell cycle regulation. The encoded protein is found in a centrosomal complex with FEZ1, a neuronal protein that plays a role in axonal development. Defects in this gene are a cause of polycystic kidney disease (PKD). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032188833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEK1	NM_001199397.3	c.2137G>T	p.Val713Leu	missense_variant, splice_region_variant	24/36	ENST00000507142.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEK1	ENST00000507142.6	c.2137G>T	p.Val713Leu	missense_variant, splice_region_variant	24/36	1	NM_001199397.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1455704 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 723526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000811

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short-rib thoracic dysplasia 6 with or without polydactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2021

This sequence change replaces valine with leucine at codon 685 of the NEK1 protein (p.Val685Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NEK1-related conditions. This variant is present in population databases (rs199827465, ExAC 0.002%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	8.5
Dann	Benign	0.82
DEOGEN2	Benign	0.035	T;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.83	T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.032	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.;.;.;.
MutationTaster	Benign	0.90	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N;N;N;N;N
REVEL	Benign	0.087
Sift	Benign	0.79	T;T;T;T;T
Sift4G	Benign	0.33	T;T;T;T;T
Polyphen		0.0030	B;.;B;B;B
Vest4		0.096
MutPred		0.096		Loss of methylation at K681 (P = 0.0864);.;.;.;.;
MVP		0.41
MPC		0.055
ClinPred		0.063	T
GERP RS		-5.2
Varity_R		0.039
gMVP		0.030

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.028
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

Other links and lift over

dbSNP: rs199827465; hg19: chr4-170400556;