Genetic Variant NM_001294338.2:c.1295G>C (chr1-155263972-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001294338.2(CLK2):c.1295G>C(p.Arg432Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R432S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CLK2
NM_001294338.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.17

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.825

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.1295G>C	p.Arg432Pro	missense	Exon 12 of 13	NP_001281267.1	P49760-1
CLK2	NM_003993.4		c.1292G>C	p.Arg431Pro	missense	Exon 12 of 13	NP_003984.2
CLK2	NM_001363704.2		c.1289G>C	p.Arg430Pro	missense	Exon 12 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.1295G>C	p.Arg432Pro	missense	Exon 12 of 13	ENSP00000357345.4	P49760-1
CLK2	ENST00000361168.9	TSL:1	c.1292G>C	p.Arg431Pro	missense	Exon 12 of 13	ENSP00000354856.5	P49760-3
CLK2	ENST00000476983.5	TSL:1	n.1336G>C		non_coding_transcript_exon	Exon 11 of 12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

PhyloP100

6.2

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.84

MutPred

0.60

Loss of MoRF binding (P = 6e-04)

MVP

0.25

MPC

1.7

ClinPred

1.0

GERP RS

4.2

Varity_R

0.97

gMVP

0.86

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over