dbSNP rs182137525: PLEK:p.Asn168Lys (chr2-68386533-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_002664.3(PLEK):c.504C>A(p.Asn168Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

PLEK
NM_002664.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.284

Publications

1 publications found

Variant links:

Genes affected

PLEK (HGNC:9070): (pleckstrin) Enables phosphatidylinositol-3,4-bisphosphate binding activity; protein homodimerization activity; and protein kinase C binding activity. Involved in several processes, including G protein-coupled receptor signaling pathway; actin cytoskeleton organization; and positive regulation of supramolecular fiber organization. Located in cytoplasm and ruffle membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLEK links:

ENSG00000301281 (HGNC:):

ENSG00000301281 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024273813).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002664.3. 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
	PLEK	NM_002664.3	MANE Select	c.504C>A	p.Asn168Lys	missense	Exon 5 of 9	NP_002655.2	P08567

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLEK	ENST00000234313.8	TSL:1 MANE Select	c.504C>A	p.Asn168Lys	missense	Exon 5 of 9	ENSP00000234313.7	P08567
	ENSG00000301281	ENST00000777616.1		n.189-3755G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251132

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33462

American (AMR)

AF:

0.0000895

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111694

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.0000854

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41506

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.0000355

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.0000330

AC:

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

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.7

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.11

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.72

M_CAP

Benign

0.0052

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.84

PhyloP100

0.28

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

REVEL

Benign

0.087

Sift

Benign

0.47

Sift4G

Benign

0.40

Polyphen

0.0010

Vest4

0.072

MutPred

0.72

Gain of methylation at N168 (P = 0.023)

MVP

0.38

MPC

0.060

ClinPred

0.0097

GERP RS

0.71

Varity_R

0.042

gMVP

0.40

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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