Genetic Variant CLK3:c.1-3555G>T (chr15-74615642-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003992.5(CLK3):c.1-3555G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000051 in 1,098,714 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: not found (cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

CLK3
NM_003992.5 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.29

Variant links:

Genes affected

CLK3 (HGNC:2071): (CDC like kinase 3) This gene encodes a protein belonging to the serine/threonine type protein kinase family. This protein is a nuclear dual-specificity kinase that regulates the intranuclear distribution of the serine/arginine-rich (SR) family of splicing factors. Two transcript variants encoding different isoforms have been found for this gene. Related pseudogenes are located on chromosomes 1 and 9. [provided by RefSeq, Jul 2008]

CLK3 links:

CLK3-AS1 (HGNC:58198):

CLK3-AS1 links:

ENSG00000260919 (HGNC:):

ENSG00000260919 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08067289).

BS2

High AC in GnomAdExome4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLK3	NM_003992.5 link	c.1-3555G>T	intron_variant	Intron 1 of 12		NP_003983.2	P49761-1
CLK3-AS1	XR_007064714.1 link	n.151C>A	non_coding_transcript_exon_variant	Exon 1 of 12
CLK3-AS1	XR_007064715.1 link	n.151C>A	non_coding_transcript_exon_variant	Exon 1 of 9
CLK3	NM_001130028.2 link	c.-257G>T	upstream_gene_variant		ENST00000395066.9	NP_001123500.2	P49761-1B3KRI8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLK3	ENST00000395066.9 link	c.-257G>T		upstream_gene_variant		1	NM_001130028.2	ENSP00000378505.4		P49761-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1098714

Hom.:

Cov.:

AF XY:

0.0000479

AC XY:

AN XY:

521942

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23010

American (AMR)

AF:

0.00

AC:

AN:

8422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14678

East Asian (EAS)

AF:

0.00

AC:

AN:

26514

South Asian (SAS)

AF:

0.00

AC:

AN:

27002

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2980

European-Non Finnish (NFE)

AF:

0.0000603

AC:

AN:

929346

Other (OTH)

AF:

0.00

AC:

AN:

44318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.188G>T (p.G63V) alteration is located in exon 1 (coding exon 1) of the CLK3 gene. This alteration results from a G to T substitution at nucleotide position 188, causing the glycine (G) at amino acid position 63 to be replaced by a valine (V). 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

Benign

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.79

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0073

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.40

M_CAP

Benign

0.026

MetaRNN

Benign

0.081

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

-1.3

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.45

Sift

Uncertain

0.0040

Sift4G

Benign

0.11

Polyphen

0.093

Vest4

0.10

MutPred

0.15

Gain of stability (P = 0.0098);

MVP

0.26

MPC

0.20

ClinPred

0.15

GERP RS

-0.43

PromoterAI

-0.055

Neutral

(source)

Varity_R

0.054

gMVP

0.050

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

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chr15-74615642-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over