rs199827465

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-169479405-C-A
• chr4-169479405-C-G
• chr4-169479405-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001199397.3(NEK1):​c.2137G>T​(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 0.00000618 in 1,455,704 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. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.0000062 (0 hom.)
• Consequence: NEK1 NM_001199397.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002512
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.032188833).

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1455704 Hom.: 0 Cov.: 30 AF XY: 0.00000553 AC XY: 4 AN XY: 723526

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: 0.00000811 AC: 9 AN: 1109540

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Short-rib thoracic dysplasia 6 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.5
DANN	Benign	0.82
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	0.019	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		0.063	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	0.00025
dbscSNV1_RF	Benign	0.028
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;