Genetic Variant CLK3:c.-47C>G (chr15-74615852-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_001130028.2(CLK3):c.-47C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000422 in 1,254,860 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 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

CLK3
NM_001130028.2 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.275

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:

LOC102723750 (HGNC:):

LOC102723750 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=0.054613084).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLK3	NM_001130028.2 link	c.-47C>G	5_prime_UTR_variant	Exon 1 of 13	ENST00000395066.9	NP_001123500.2	P49761-1B3KRI8
CLK3	NM_003992.5 link	c.1-3345C>G	intron_variant	Intron 1 of 12		NP_003983.2	P49761-1
LOC102723750	XR_007064714.1 link	n.-60G>C	upstream_gene_variant
LOC102723750	XR_007064715.1 link	n.-60G>C	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLK3	ENST00000395066 link	c.-47C>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_001130028.2	ENSP00000378505.4		P49761-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

13280

Hom.:

AF XY:

0.00

AC XY:

AN XY:

7450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000258

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000435

AC:

AN:

1102714

Hom.:

Cov.:

AF XY:

0.0000439

AC XY:

AN XY:

524422

show subpopulations

Gnomad4 AFR exome

AF:

0.0000423

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000494

Gnomad4 OTH exome

AF:

0.0000225

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000513

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.398C>G (p.A133G) alteration is located in exon 1 (coding exon 1) of the CLK3 gene. This alteration results from a C to G substitution at nucleotide position 398, causing the alanine (A) at amino acid position 133 to be replaced by a glycine (G). 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

0.065

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0062

T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.41

T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.52

N;N

Sift

Uncertain

0.0080

D;D

Sift4G

Benign

0.34

T;D

Polyphen

0.022

B;.

Vest4

0.045

MVP

0.46

MPC

0.16

ClinPred

0.096

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

gMVP

0.031

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

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