15-74615659-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000345005.8(CLK3):c.1-3538G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,094,652 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: 9.1e-7 (0 hom.)
• Consequence: CLK3 ENST00000345005.8 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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]

LOC102723750 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07292402).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LOC102723750	XR_007064714.1	n.134C>T		non_coding_transcript_exon_variant	1/12
CLK3	NM_003992.5	c.1-3538G>A		intron_variant
LOC102723750	XR_007064715.1	n.134C>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLK3	ENST00000345005.8	c.1-3538G>A		intron_variant		1		P1
CLK3	ENST00000562389.5	c.-1+610G>A		intron_variant		4
CLK3	ENST00000483723.5	c.1-3538G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1094652 Hom.: 0 Cov.: 30 AF XY: 0.00000193 AC XY: 1 AN XY: 519366

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: 0.00000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The c.205G>A (p.G69S) 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 205, causing the glycine (G) at amino acid position 69 to be replaced by a serine (S). 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	-0.14	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	8.9
Dann	Benign	0.96
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.35	N
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.34	T
Polyphen		0.076	B
Vest4		0.071
MutPred		0.16		Gain of phosphorylation at G69 (P = 0.0047);
MVP		0.29
MPC		0.16
ClinPred		0.15	T
GERP RS		-0.39
Varity_R		0.055
gMVP		0.063

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.

Other links and lift over

hg19: chr15-74908000;