CRKL

protein-coding

CRK like proto-oncogene, adaptor protein, the group of SH2 domain containing

Gene summary

This gene encodes a protein kinase containing SH2 and SH3 (src homology) domains which has been shown to activate the RAS and JUN kinase signaling pathways and transform fibroblasts in a RAS-dependent fashion. It is a substrate of the BCR-ABL tyrosine kinase, plays a role in fibroblast transformation by BCR-ABL, and may be oncogenic.[provided by RefSeq, Jan 2009]

MANE transcript

NM_005207.4

Inheritance

—

ClinVar variants

U:25B:27

Top phenotype

CRKL-related disorder

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr22:20,917,407-20,953,747

External References & Databases

Ensembl (ENSG00000099942)

Transcript & Mutation Effects

hg38 • Region Span ~36.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseNO_KNOWN

Inheritance Pattern: Unknown

Disease ID:MONDO:0005453

Submitter: ClinGen

*CRKL* was first reported in relation to congenital heart disease in 2012 (Tomita Mitchell et al., PMID:22318994). Seven probands with CNVs (4 duplications, 3 gross deletions) at the 22q11.2 location have been reported in 3 publications (PMID: 22318994, 28121514, 36205932). No evidence for a causal role for *CRKL* in congenital heart disease has been reported. Although this gene-disease association is supported by an animal model, no reports have directly implicated the gene in humans. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 10/17/2023 (SOP Version 9)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRKL variants in ClinVar

3 Conditions Cataloged

not providedTotal: 41

not specifiedTotal: 23

CRKL-related disorderTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005207.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				25 clinvar	1 clinvar	26
missense			22 clinvar		1 clinvar	23
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	25	25	2	52

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005207.4	RefSeq	NP_005198.1	3	MANE Select
ENST00000354336.8	Ensembl	ENSP00000346300.3	3	MANE Select
ENST00000411769.1	Ensembl	ENSP00000396646.1	3	Standard
ENST00000894699.1	Ensembl	ENSP00000564758.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
crkl	Danio rerio	Structure: fast muscle cell Quality: mononucleate abnormal

Gene / Model

Organism

Observed Phenotype

crkl

Danio rerio

Structure: fast muscle cell

Quality: mononucleate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Chronic myeloid leukemia - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
Fc gamma R-mediated phagocytosis - Homo sapiens (human)
Renal cell carcinoma - Homo sapiens (human)
Neurotrophin signaling pathway - Homo sapiens (human)

Biological Process

activation of MAPKK activity
activation of MAPK activity
regulation of cell growth
blood vessel development
urogenital system development

Molecular Function

phosphotyrosine residue binding
RNA binding
SH3/SH2 adaptor activity
protein binding
identical protein binding

Cellular Component

nucleoplasm
cytosol
neuromuscular junction
protein-containing complex
extrinsic component of postsynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354336
Coding exons: 3
Length: 36324
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125744
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.94	105	178	0.591	0.00000943	1973
Missense (PolyPhen)		23	68.177	0.33736		767
Synonymous	-2.03	98	75.6	1.30	0.00000447	633
Loss of Function	2.31	2	9.82	0.204	4.23e-7	118

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May mediate the transduction of intracellular signals.;

Recessive Scores

pRec: 0.440

Intolerance Scores

LoFtool: 0.0613
RVIS EVS: -0.32
RVIS percentile EVS: 31.46

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium