Genetic Variant CLK2:p.His269Asn (chr1-155266762-G-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001294338.2(CLK2):c.805C>A(p.His269Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,613,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

CLK2
NM_001294338.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

1 publications found

Variant links:

Genes affected

CLK2 (HGNC:2069): (CDC like kinase 2) This gene encodes a dual specificity protein kinase that phosphorylates serine/threonine and tyrosine-containing substrates. Activity of this protein regulates serine- and arginine-rich (SR) proteins of the spliceosomal complex, thereby influencing alternative transcript splicing. Chromosomal translocations have been characterized between this locus and the PAFAH1B3 (platelet-activating factor acetylhydrolase 1b, catalytic subunit 3 (29kDa)) gene on chromosome 19, resulting in the production of a fusion protein. Note that this gene is distinct from the TELO2 gene (GeneID:9894), which shares the CLK2 alias, but encodes a protein that is involved in telomere length regulation. There is a pseudogene for this gene on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

CLK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40048277).

BS2

High AC in GnomAd4 at 12 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001294338.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLK2	NM_001294338.2	MANE Select	c.805C>A	p.His269Asn	missense	Exon 7 of 13	NP_001281267.1	P49760-1
CLK2	NM_003993.4		c.802C>A	p.His268Asn	missense	Exon 7 of 13	NP_003984.2
CLK2	NM_001363704.2		c.799C>A	p.His267Asn	missense	Exon 7 of 13	NP_001350633.1	B1AVT0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLK2	ENST00000368361.9	TSL:1 MANE Select	c.805C>A	p.His269Asn	missense	Exon 7 of 13	ENSP00000357345.4	P49760-1
CLK2	ENST00000361168.9	TSL:1	c.802C>A	p.His268Asn	missense	Exon 7 of 13	ENSP00000354856.5	P49760-3
CLK2	ENST00000476983.5	TSL:1	n.846C>A		non_coding_transcript_exon	Exon 6 of 12

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000957

AC:

AN:

250694

AF XY:

0.000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461134

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726852

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33452

American (AMR)

AF:

0.000134

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.0000792

AC:

AN:

1111730

Other (OTH)

AF:

0.000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000788

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00316

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68030

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

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:

0.000116

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

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

0.20

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.022

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.88

MutationAssessor

Benign

-0.065

PhyloP100

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.35

Sift

Benign

0.13

Sift4G

Benign

0.095

Polyphen

0.26

Vest4

0.61

MVP

0.52

MPC

1.8

ClinPred

0.16

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.83

gMVP

0.72

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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