4-169479405-C-G

Variant names:

• chr4-169479405-C-G
• rs199827465
• NM_001199397.3:c.2137G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001199397.3(NEK1):​c.2137G>C​(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 0.00000343 in 1,455,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 19/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V713M) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NEK1 NM_001199397.3 missense, splice_region
• Scores: Splicing: ADA: 0.00008104
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.180
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03206563).

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.2137G>C	p.Val713Leu	missense splice_region	Exon 24 of 36	NP_001186326.1
	NEK1	NM_001374418.1		c.2137G>C	p.Val713Leu	missense splice_region	Exon 23 of 35	NP_001361347.1
	NEK1	NM_001374419.1		c.2053G>C	p.Val685Leu	missense splice_region	Exon 23 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.2137G>C	p.Val713Leu	missense splice_region	Exon 24 of 36	ENSP00000424757.2
	NEK1	ENST00000439128.6	TSL:1	c.2053G>C	p.Val685Leu	missense splice_region	Exon 22 of 34	ENSP00000408020.2
	NEK1	ENST00000511633.5	TSL:1	c.2005G>C	p.Val669Leu	missense splice_region	Exon 23 of 35	ENSP00000423332.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245916 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1455706 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 723526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 83900

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109542

Other (OTH) AF: 0.00 AC: 0 AN: 60174

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000167064), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	7.4
DANN	Benign	0.85
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
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.18
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.087
Sift	Benign	0.79	T
Sift4G	Benign	0.33	T
Polyphen		0.0030	B
Vest4		0.096
MutPred		0.096		Loss of methylation at K681 (P = 0.0864)
MVP		0.41
MPC		0.055
ClinPred		0.075	T
GERP RS		-5.2
Varity_R		0.039
gMVP		0.030
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000081
dbscSNV1_RF	Benign	0.0060
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: rs199827465; hg19: chr4-170400556;