1-155266762-G-A

Variant names:

• chr1-155266762-G-A
• rs145678484
• NM_001294338.2:c.805C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001294338.2(CLK2):​c.805C>T​(p.His269Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,136 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H269N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLK2 NM_001294338.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

CLK2 (HGNC:2069): (CDC like kinase 2) This gene encodes a dual specificity protein kinase that phosphorylates serine/threonine and tyrosine-containing substrates. Activity of this protein regulates serine- and arginine-rich (SR) proteins of the spliceosomal complex, thereby influencing alternative transcript splicing. Chromosomal translocations have been characterized between this locus and the PAFAH1B3 (platelet-activating factor acetylhydrolase 1b, catalytic subunit 3 (29kDa)) gene on chromosome 19, resulting in the production of a fusion protein. Note that this gene is distinct from the TELO2 gene (GeneID:9894), which shares the CLK2 alias, but encodes a protein that is involved in telomere length regulation. There is a pseudogene for this gene on chromosome 7. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001294338.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLK2	NM_001294338.2	MANE Select	c.805C>T	p.His269Tyr	missense	Exon 7 of 13	NP_001281267.1	P49760-1
	CLK2	NM_003993.4		c.802C>T	p.His268Tyr	missense	Exon 7 of 13	NP_003984.2
	CLK2	NM_001363704.2		c.799C>T	p.His267Tyr	missense	Exon 7 of 13	NP_001350633.1	B1AVT0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLK2	ENST00000368361.9	TSL:1 MANE Select	c.805C>T	p.His269Tyr	missense	Exon 7 of 13	ENSP00000357345.4	P49760-1
	CLK2	ENST00000361168.9	TSL:1	c.802C>T	p.His268Tyr	missense	Exon 7 of 13	ENSP00000354856.5	P49760-3
	CLK2	ENST00000476983.5	TSL:1	n.846C>T		non_coding_transcript_exon	Exon 6 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726854

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111732

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.38	N
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.41
Sift	Benign	0.042	D
Sift4G	Benign	0.14	T
Polyphen		0.60	P
Vest4		0.54
MutPred		0.53		Gain of catalytic residue at H269 (P = 0.1209)
MVP		0.50
MPC		2.1
ClinPred		0.98	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.79
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145678484; hg19: chr1-155236553;