chr15-74615720-C-G

Variant names:

• chr15-74615720-C-G
• rs1356912577
• ENST00000345005.8:c.1-3477C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003992.5(CLK3):​c.1-3477C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000565 in 1,238,688 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 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CLK3 NM_003992.5 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.619

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-AS1 (HGNC:58198):

ENSG00000260919 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.07908723).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLK3	NM_003992.5	c.1-3477C>G		intron_variant	Intron 1 of 12		NP_003983.2
CLK3-AS1	XR_007064714.1	n.73G>C		non_coding_transcript_exon_variant	Exon 1 of 12
CLK3-AS1	XR_007064715.1	n.73G>C		non_coding_transcript_exon_variant	Exon 1 of 9
CLK3	NM_001130028.2	c.-179C>G		upstream_gene_variant		ENST00000395066.9	NP_001123500.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLK3	ENST00000395066.9	c.-179C>G		upstream_gene_variant		1	NM_001130028.2	ENSP00000378505.4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000552 AC: 6 AN: 1086492 Hom.: 0 Cov.: 30 AF XY: 0.00000389 AC XY: 2 AN XY: 514154

African (AFR) AF: 0.00 AC: 0 AN: 22952

American (AMR) AF: 0.00 AC: 0 AN: 8396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14460

East Asian (EAS) AF: 0.00 AC: 0 AN: 26488

South Asian (SAS) AF: 0.0000885 AC: 2 AN: 22600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2950

European-Non Finnish (NFE) AF: 0.00000217 AC: 2 AN: 923198

Other (OTH) AF: 0.0000456 AC: 2 AN: 43898

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.266C>G (p.P89R) 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 266, causing the proline (P) at amino acid position 89 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.36	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.62
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.21	N
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.093	B
Vest4		0.11
MutPred		0.26		Gain of solvent accessibility (P = 0.007);
MVP		0.23
MPC		0.17
ClinPred		0.34	T
GERP RS		1.8
PromoterAI		0.019	Neutral
Varity_R		0.091
gMVP		0.083

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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Other links and lift over

dbSNP: rs1356912577; hg19: chr15-74908061;