rs34324114

Variant names:

• chr4-169477323-A-C
• rs34324114
• NM_001199397.3:c.2235T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-169477323-A-C
• chr4-169477323-A-T

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.2235T>G​(p.Asn745Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,578,452 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (40 hom.)
• Consequence: NEK1 NM_001199397.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.06
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008582711).
• BP6: Variant 4-169477323-A-C is Benign according to our data. Variant chr4-169477323-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266051.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00406 (618/152102) while in subpopulation NFE AF = 0.00596 (405/67902). AF 95% confidence interval is 0.00549. There are 2 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	NM_001199397.3	MANE Select	c.2235T>G	p.Asn745Lys	missense	Exon 26 of 36	NP_001186326.1
	NEK1	NM_001374418.1		c.2235T>G	p.Asn745Lys	missense	Exon 25 of 35	NP_001361347.1
	NEK1	NM_001374419.1		c.2151T>G	p.Asn717Lys	missense	Exon 25 of 35	NP_001361348.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEK1	ENST00000507142.6	TSL:1 MANE Select	c.2235T>G	p.Asn745Lys	missense	Exon 26 of 36	ENSP00000424757.2
	NEK1	ENST00000439128.6	TSL:1	c.2151T>G	p.Asn717Lys	missense	Exon 24 of 34	ENSP00000408020.2
	NEK1	ENST00000511633.5	TSL:1	c.2103T>G	p.Asn701Lys	missense	Exon 25 of 35	ENSP00000423332.1

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 618 AN: 151984 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.000722

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0144

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00596

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00465 AC: 919 AN: 197656 AF XY: 0.00457

Gnomad AFR exome AF: 0.000712

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00262

Gnomad EAS exome AF: 0.0000701

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.00601

Gnomad OTH exome AF: 0.00451

GnomAD4 exome AF: 0.00541 AC: 7714 AN: 1426350 Hom.: 40 Cov.: 31 AF XY: 0.00541 AC XY: 3819 AN XY: 706542

African (AFR) AF: 0.000551 AC: 18 AN: 32666

American (AMR) AF: 0.000428 AC: 17 AN: 39732

Ashkenazi Jewish (ASJ) AF: 0.00254 AC: 65 AN: 25556

East Asian (EAS) AF: 0.0000261 AC: 1 AN: 38338

South Asian (SAS) AF: 0.00193 AC: 158 AN: 81784

European-Finnish (FIN) AF: 0.0147 AC: 753 AN: 51320

Middle Eastern (MID) AF: 0.00123 AC: 7 AN: 5704

European-Non Finnish (NFE) AF: 0.00595 AC: 6501 AN: 1092322

Other (OTH) AF: 0.00329 AC: 194 AN: 58928

GnomAD4 genome AF: 0.00406 AC: 618 AN: 152102 Hom.: 2 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74394

African (AFR) AF: 0.000602 AC: 25 AN: 41550

American (AMR) AF: 0.000721 AC: 11 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4828

European-Finnish (FIN) AF: 0.0144 AC: 153 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00596 AC: 405 AN: 67902

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00454 Hom.: 7

Bravo AF: 0.00296

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00111 AC: 4

ESP6500EA AF: 0.00579 AC: 47

ExAC AF: 0.00379 AC: 453

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	Short-rib thoracic dysplasia 6 with or without polydactyly (3)
-	1	-	Motor neuron disease (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.77
MutPred		0.12		Gain of ubiquitination at N717 (P = 0.0162)
MVP		0.93
MPC		0.38
ClinPred		0.036	T
GERP RS		5.6
Varity_R		0.71
gMVP		0.52
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34324114; hg19: chr4-170398474;