4-169585374-C-T

Variant names:

• chr4-169585374-C-T
• rs200161705
• NM_001199397.3:c.782G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001199397.3(NEK1):​c.782G>A​(p.Arg261His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,048 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R261C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (10 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7 O:1
• Conservation: PhyloP100: 7.80
• Publications: 35 publications found

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]

NEK1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis, susceptibility to, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• short-rib thoracic dysplasia 6 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• orofaciodigital syndrome type II

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Majewski type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04310599).
• BP6: Variant 4-169585374-C-T is Benign according to our data. Variant chr4-169585374-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 199125.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00215 (327/152232) while in subpopulation NFE AF = 0.00391 (266/68002). AF 95% confidence interval is 0.00353. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199397.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	NM_001199397.3	MANE Select	c.782G>A	p.Arg261His	missense	Exon 10 of 36	NP_001186326.1	Q96PY6-3
	NEK1	NM_001374418.1		c.782G>A	p.Arg261His	missense	Exon 9 of 35	NP_001361347.1	Q96PY6-3
	NEK1	NM_001374419.1		c.782G>A	p.Arg261His	missense	Exon 10 of 35	NP_001361348.1	Q96PY6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	ENST00000507142.6	TSL:1 MANE Select	c.782G>A	p.Arg261His	missense	Exon 10 of 36	ENSP00000424757.2	Q96PY6-3
	NEK1	ENST00000439128.6	TSL:1	c.782G>A	p.Arg261His	missense	Exon 9 of 34	ENSP00000408020.2	Q96PY6-1
	NEK1	ENST00000511633.5	TSL:1	c.782G>A	p.Arg261His	missense	Exon 10 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 327 AN: 152114 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00229 AC: 570 AN: 248534 AF XY: 0.00215

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00392

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00271 AC: 3955 AN: 1460816 Hom.: 10 Cov.: 30 AF XY: 0.00267 AC XY: 1942 AN XY: 726676

African (AFR) AF: 0.000777 AC: 26 AN: 33444

American (AMR) AF: 0.00117 AC: 52 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.000894 AC: 77 AN: 86130

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53380

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.00322 AC: 3576 AN: 1111404

Other (OTH) AF: 0.00216 AC: 130 AN: 60318

GnomAD4 genome AF: 0.00215 AC: 327 AN: 152232 Hom.: 1 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74440

African (AFR) AF: 0.000530 AC: 22 AN: 41542

American (AMR) AF: 0.00111 AC: 17 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00331 Hom.: 3

Bravo AF: 0.00212

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000821 AC: 3

ESP6500EA AF: 0.00380 AC: 31

ExAC AF: 0.00229 AC: 276

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00437

EpiControl AF: 0.00332

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	2	Short-rib thoracic dysplasia 6 with or without polydactyly (2)
-	1	-	Motor neuron disease (1)
-	-	1	NEK1-related disorder (1)
-	-	-	Amyotrophic lateral sclerosis, susceptibility to, 24 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.26
Sift	Benign	0.044	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.86
MVP		0.52
MPC		0.38
ClinPred		0.039	T
GERP RS		5.8
Varity_R		0.48
gMVP		0.73
Mutation Taster		=96/4	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200161705; hg19: chr4-170506525;