chr4-169438116-G-C

Variant names:

• chr4-169438116-G-C
• rs6828134
• NM_001199397.3:c.2731C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199397.3(NEK1):​c.2731C>G​(p.Gln911Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,612,356 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (6 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.39
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032262504).
• BP6: Variant 4-169438116-G-C is Benign according to our data. Variant chr4-169438116-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 527126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00489 (745/152324) while in subpopulation AFR AF = 0.0173 (721/41566). AF 95% confidence interval is 0.0163. There are 5 homozygotes in GnomAd4. There are 338 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	NM_001199397.3	MANE Select	c.2731C>G	p.Gln911Glu	missense	Exon 28 of 36	NP_001186326.1
	NEK1	NM_001374418.1		c.2731C>G	p.Gln911Glu	missense	Exon 27 of 35	NP_001361347.1
	NEK1	NM_001374419.1		c.2647C>G	p.Gln883Glu	missense	Exon 27 of 35	NP_001361348.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	ENST00000507142.6	TSL:1 MANE Select	c.2731C>G	p.Gln911Glu	missense	Exon 28 of 36	ENSP00000424757.2
	NEK1	ENST00000439128.6	TSL:1	c.2647C>G	p.Gln883Glu	missense	Exon 26 of 34	ENSP00000408020.2
	NEK1	ENST00000511633.5	TSL:1	c.2599C>G	p.Gln867Glu	missense	Exon 27 of 35	ENSP00000423332.1

Frequencies

GnomAD3 genomes AF: 0.00489 AC: 745 AN: 152206 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00119 AC: 293 AN: 246646 AF XY: 0.000906

Gnomad AFR exome AF: 0.0176

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000500

GnomAD4 exome AF: 0.000511 AC: 746 AN: 1460032 Hom.: 6 Cov.: 30 AF XY: 0.000461 AC XY: 335 AN XY: 726048

African (AFR) AF: 0.0183 AC: 614 AN: 33466

American (AMR) AF: 0.000539 AC: 24 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000933 AC: 8 AN: 85702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111188

Other (OTH) AF: 0.00116 AC: 70 AN: 60320

GnomAD4 genome AF: 0.00489 AC: 745 AN: 152324 Hom.: 5 Cov.: 33 AF XY: 0.00454 AC XY: 338 AN XY: 74486

African (AFR) AF: 0.0173 AC: 721 AN: 41566

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000699 Hom.: 2

Bravo AF: 0.00570

ESP6500AA AF: 0.0161 AC: 59

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00151 AC: 182

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Connective tissue disorder (1)
-	-	1	Short-rib thoracic dysplasia 6 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.62
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.16
Sift	Benign	0.27	T
Sift4G	Benign	0.51	T
Polyphen		0.0010	B
Vest4		0.089
MVP		0.67
MPC		0.058
ClinPred		0.017	T
GERP RS		4.2
Varity_R		0.080
gMVP		0.057
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs6828134; hg19: chr4-170359267; COSMIC: COSV99073142;