1-155268012-C-G

Position:

chr1-155268012-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001294338.2(CLK2):c.669G>C(p.Lys223Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,610,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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 (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

CLK2
NM_001294338.2 missense, splice_region

Scores

Splicing: ADA: 0.001364

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058562458).

BS2

High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLK2	NM_001294338.2 linkuse as main transcript	c.669G>C	p.Lys223Asn	missense_variant, splice_region_variant	6/13	ENST00000368361.9	NP_001281267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLK2	ENST00000368361.9 linkuse as main transcript	c.669G>C	p.Lys223Asn	missense_variant, splice_region_variant	6/13	1	NM_001294338.2	ENSP00000357345	P4	P49760-1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251402

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1458800

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

725956

show subpopulations

Gnomad4 AFR exome

AF:

0.000778

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.01e-7

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000250

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000869

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000503

Hom.:

Bravo

AF:

0.000272

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.666G>C (p.K222N) alteration is located in exon 6 (coding exon 5) of the CLK2 gene. This alteration results from a G to C substitution at nucleotide position 666, causing the lysine (K) at amino acid position 222 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

.;T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.0062

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.4

N;N;N

REVEL

Benign

0.030

Sift

Benign

0.087

T;T;T

Sift4G

Benign

0.10

T;T;T

Polyphen

0.016

B;B;.

Vest4

0.28

MutPred

0.52

.;Loss of ubiquitination at K223 (P = 0.011);.;

MVP

0.33

MPC

1.4

ClinPred

0.026

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.010

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over