chr4-169562196-C-T

Variant names:

• chr4-169562196-C-T
• rs189186475
• NM_001199397.3:c.1021G>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.1021G>A​(p.Ala341Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,527,934 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (8 hom.)
• Consequence: NEK1 NM_001199397.3 missense, splice_region
• Scores: Splicing: ADA: 0.4484
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 1.28
• Publications: 5 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=0.0074309707).
• BP6: Variant 4-169562196-C-T is Benign according to our data. Variant chr4-169562196-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 266046.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00215 (326/151792) while in subpopulation NFE AF = 0.00337 (229/67890). AF 95% confidence interval is 0.00301. There are 1 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.1021G>A	p.Ala341Thr	missense splice_region	Exon 13 of 36	NP_001186326.1	Q96PY6-3
	NEK1	NM_001374418.1		c.1021G>A	p.Ala341Thr	missense splice_region	Exon 12 of 35	NP_001361347.1	Q96PY6-3
	NEK1	NM_001374419.1		c.1021G>A	p.Ala341Thr	missense splice_region	Exon 13 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.1021G>A	p.Ala341Thr	missense splice_region	Exon 13 of 36	ENSP00000424757.2	Q96PY6-3
	NEK1	ENST00000439128.6	TSL:1	c.1021G>A	p.Ala341Thr	missense splice_region	Exon 12 of 34	ENSP00000408020.2	Q96PY6-1
	NEK1	ENST00000511633.5	TSL:1	c.1021G>A	p.Ala341Thr	missense splice_region	Exon 13 of 35	ENSP00000423332.1	Q96PY6-6

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 326 AN: 151676 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00440

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00167 AC: 248 AN: 148168 AF XY: 0.00136

Gnomad AFR exome AF: 0.000641

Gnomad AMR exome AF: 0.000932

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00282

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00306 AC: 4217 AN: 1376142 Hom.: 8 Cov.: 27 AF XY: 0.00299 AC XY: 2028 AN XY: 678660

African (AFR) AF: 0.000430 AC: 13 AN: 30246

American (AMR) AF: 0.00115 AC: 37 AN: 32192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24604

East Asian (EAS) AF: 0.00 AC: 0 AN: 35684

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73410

European-Finnish (FIN) AF: 0.00264 AC: 130 AN: 49334

Middle Eastern (MID) AF: 0.000533 AC: 3 AN: 5628

European-Non Finnish (NFE) AF: 0.00364 AC: 3890 AN: 1068032

Other (OTH) AF: 0.00251 AC: 143 AN: 57012

GnomAD4 genome AF: 0.00215 AC: 326 AN: 151792 Hom.: 1 Cov.: 32 AF XY: 0.00214 AC XY: 159 AN XY: 74158

African (AFR) AF: 0.000772 AC: 32 AN: 41442

American (AMR) AF: 0.000787 AC: 12 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00440 AC: 46 AN: 10462

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

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 67890

Other (OTH) AF: 0.00333 AC: 7 AN: 2104

Alfa AF: 0.00231 Hom.: 0

Bravo AF: 0.00190

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000284 AC: 1

ESP6500EA AF: 0.00236 AC: 19

ExAC AF: 0.000717 AC: 80

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	1	1	Short-rib thoracic dysplasia 6 with or without polydactyly (2)
-	-	1	Connective tissue disorder (1)
-	1	-	Motor neuron disease (1)
-	-	1	NEK1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	0.0031
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.3
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Benign	0.037	D
Sift4G	Uncertain	0.031	D
Polyphen		0.13	B
Vest4		0.067
MVP		0.67
MPC		0.078
ClinPred		0.012	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.23
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.45
dbscSNV1_RF	Benign	0.41
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: rs189186475; hg19: chr4-170483347; COSMIC: COSV71454463;