Genetic Variant NEK5:p.Gly426Val (chr13-52087453-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001365552.1(NEK5):c.1277G>T(p.Gly426Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000146 in 1,366,580 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

NEK5
NM_001365552.1 missense, splice_region

Scores

Splicing: ADA: 0.9743

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.81

Publications

2 publications found

Variant links:

Genes affected

NEK5 (HGNC:7748): (NIMA related kinase 5) Predicted to enable ATP binding activity; metal ion binding activity; and protein kinase activity. Predicted to be involved in protein phosphorylation. Predicted to act upstream of or within positive regulation of cysteine-type endopeptidase activity and positive regulation of striated muscle cell differentiation. [provided by Alliance of Genome Resources, Apr 2022]

NEK5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365552.1. 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
	NEK5	NM_001365552.1	MANE Select	c.1277G>T	p.Gly426Val	missense splice_region	Exon 15 of 24	NP_001352481.1	A0A8I5KQI9
	NEK5	NM_199289.3		c.1277G>T	p.Gly426Val	missense splice_region	Exon 15 of 22	NP_954983.1	Q6P3R8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NEK5	ENST00000684899.1	MANE Select	c.1277G>T	p.Gly426Val	missense splice_region	Exon 15 of 24	ENSP00000509632.1	A0A8I5KQI9
NEK5	ENST00000355568.8	TSL:1	c.1277G>T	p.Gly426Val	missense splice_region	Exon 15 of 22	ENSP00000347767.4	Q6P3R8
NEK5	ENST00000647945.2		c.1277G>T	p.Gly426Val	missense splice_region	Exon 15 of 25	ENSP00000497892.1	A0A3B3ITQ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1366580

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

684070

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31176

American (AMR)

AF:

0.00

AC:

AN:

42382

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

39194

South Asian (SAS)

AF:

0.00

AC:

AN:

80762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5542

European-Non Finnish (NFE)

AF:

0.00000194

AC:

AN:

1032454

Other (OTH)

AF:

0.00

AC:

AN:

56960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.055

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.23

MutationAssessor

Uncertain

2.5

PhyloP100

3.8

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.4

REVEL

Uncertain

0.38

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.65

MutPred

0.26

Loss of helix (P = 0.079)

MVP

0.93

MPC

0.41

ClinPred

1.0

GERP RS

5.5

Varity_R

0.81

gMVP

0.26

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.83

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over