NM_004071.4:c.1345C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6_Moderate

The NM_004071.4(CLK1):c.1345C>T(p.Arg449Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,606,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R449H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

CLK1
NM_004071.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.50

Publications

4 publications found

Variant links:

Genes affected

CLK1 (HGNC:2068): (CDC like kinase 1) This gene encodes a member of the CDC2-like (or LAMMER) family of dual specificity protein kinases. In the nucleus, the encoded protein phosphorylates serine/arginine-rich proteins involved in pre-mRNA processing, releasing them into the nucleoplasm. The choice of splice sites during pre-mRNA processing may be regulated by the concentration of transacting factors, including serine/arginine rich proteins. Therefore, the encoded protein may play an indirect role in governing splice site selection. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

CLK1 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=0.07757145).

BP6

Variant 2-200853416-G-A is Benign according to our data. Variant chr2-200853416-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3145863.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004071.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLK1	NM_004071.4	MANE Select	c.1345C>T	p.Arg449Cys	missense	Exon 13 of 13	NP_004062.2	P49759-1
CLK1	NM_001162407.1		c.1471C>T	p.Arg491Cys	missense	Exon 13 of 13	NP_001155879.1	P49759-3
CLK1	NR_027855.2		n.1349C>T		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLK1	ENST00000321356.9	TSL:1 MANE Select	c.1345C>T	p.Arg449Cys	missense	Exon 13 of 13	ENSP00000326830.4	P49759-1
CLK1	ENST00000432425.5	TSL:1	n.*843C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000400487.1	P49759-2
CLK1	ENST00000473565.5	TSL:1	n.2873C>T		non_coding_transcript_exon	Exon 11 of 11

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000894

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.0000866

AC:

AN:

242596

AF XY:

0.0000153

show subpopulations

Gnomad AFR exome

AF:

0.000993

Gnomad AMR exome

AF:

0.000124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1454334

Hom.:

Cov.:

AF XY:

0.0000221

AC XY:

AN XY:

723144

show subpopulations

African (AFR)

AF:

0.000605

AC:

AN:

33048

American (AMR)

AF:

0.0000937

AC:

AN:

42676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0000119

AC:

AN:

84118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53024

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1110148

Other (OTH)

AF:

0.0000666

AC:

AN:

60098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.000322

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74276

show subpopulations

African (AFR)

AF:

0.000894

AC:

AN:

41394

American (AMR)

AF:

0.000655

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000192

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000838

Hom.:

Bravo

AF:

0.000400

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.068

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.17

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.63

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.86

PhyloP100

2.5

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.20

Sift

Benign

0.042

Sift4G

Uncertain

0.023

Polyphen

0.94

Vest4

0.083

MVP

0.65

MPC

0.89

ClinPred

0.12

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.26

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.20

Position offset: -21

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over