Genetic Variant CLK3:c.1-3498G>A (chr15-74615699-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_003992.5(CLK3):c.1-3498G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,086,332 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: 0.0000064 ( 0 hom. )

Consequence

CLK3
NM_003992.5 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -5.87

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06399959).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLK3	NM_003992.5 link	c.1-3498G>A	intron_variant	Intron 1 of 12		NP_003983.2	P49761-1
LOC102723750	XR_007064714.1 link	n.94C>T	non_coding_transcript_exon_variant	Exon 1 of 12
LOC102723750	XR_007064715.1 link	n.94C>T	non_coding_transcript_exon_variant	Exon 1 of 9
CLK3	NM_001130028.2 link	c.-200G>A	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.-200G>A		upstream_gene_variant		1	NM_001130028.2	ENSP00000378505.4		P49761-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000644

AC:

AN:

1086332

Hom.:

Cov.:

AF XY:

0.00000584

AC XY:

AN XY:

514118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000758

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245G>A (p.R82Q) alteration is located in exon 1 (coding exon 1) of the CLK3 gene. This alteration results from a G to A substitution at nucleotide position 245, causing the arginine (R) at amino acid position 82 to be replaced by a glutamine (Q). 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

0.096

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.15

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0063

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.53

M_CAP

Benign

0.026

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.030

Sift

Benign

0.10

Sift4G

Benign

0.35

Polyphen

0.017

Vest4

0.049

MutPred

0.20

Loss of MoRF binding (P = 0.0506);

MVP

0.45

MPC

0.19

ClinPred

0.10

GERP RS

-4.4

Varity_R

0.036

gMVP

0.061

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over