Genetic Variant NEK5:p.Gly426Asp (chr13-52087453-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001365552.1(NEK5):c.1277G>A(p.Gly426Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000171 in 1,518,648 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G426V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NEK5
NM_001365552.1 missense, splice_region

Scores

Splicing: ADA: 0.9602

Clinical Significance

Not reported in ClinVar

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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>A	p.Gly426Asp	missense splice_region	Exon 15 of 24	NP_001352481.1	A0A8I5KQI9
	NEK5	NM_199289.3		c.1277G>A	p.Gly426Asp	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>A	p.Gly426Asp	missense splice_region	Exon 15 of 24	ENSP00000509632.1	A0A8I5KQI9
NEK5	ENST00000355568.8	TSL:1	c.1277G>A	p.Gly426Asp	missense splice_region	Exon 15 of 22	ENSP00000347767.4	Q6P3R8
NEK5	ENST00000647945.2		c.1277G>A	p.Gly426Asp	missense splice_region	Exon 15 of 25	ENSP00000497892.1	A0A3B3ITQ6

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000165

AC:

AN:

243048

AF XY:

0.0000229

show subpopulations

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:

0.0000358

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1366580

Hom.:

Cov.:

AF XY:

0.0000175

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:

0.0000184

AC:

AN:

1032454

Other (OTH)

AF:

0.00

AC:

AN:

56960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.528

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

AF:

0.0000460

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

0.0023

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.86

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.64

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.5

PhyloP100

3.8

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.3

REVEL

Benign

0.28

Sift

Uncertain

0.0050

Sift4G

Benign

0.15

Polyphen

1.0

Vest4

0.59

MVP

0.91

MPC

0.34

ClinPred

0.98

GERP RS

5.5

Varity_R

0.70

gMVP

0.14

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Benign

0.68

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over