CNKSR2

connector enhancer of kinase suppressor of Ras 2, the group of PDZ domain containing|Sterile alpha motif domain containing|Pleckstrin homology domain containing

Basic information

Region (hg38): X:21372801-21654695

Links

ENSG00000149970 ∙ NCBI:22866 ∙ OMIM:300724 ∙ HGNC:19701 ∙ Uniprot:Q8WXI2 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
• intellectual disability, X-linked, syndromic, Houge type (Strong), mode of inheritance: XL
• X-linked complex neurodevelopmental disorder (Definitive), mode of inheritance: XL
• intellectual disability, X-linked, syndromic, Houge type (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked, syndromic, Houge type	XL	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	25223753; 28098945

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CNKSR2 gene.

• not_provided (132 variants)
• Inborn_genetic_diseases (58 variants)
• Intellectual_disability,_X-linked,_syndromic,_Houge_type (52 variants)
• CNKSR2-related_disorder (10 variants)
• not_specified (10 variants)
• Intellectual_disability (5 variants)
• Neurodevelopmental_disorder (1 variants)
• X-linked_recessive_seizure_and_neurodevelopmental_deficit (1 variants)
• See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CNKSR2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000014927.5. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	19	4	26
missense		3	138	12	1	154
nonsense	14	6				20
start loss						0
frameshift	16	2	1			19
splice donor/acceptor (+/-2bp)	5	5	2			12
Total	35	16	144	31	5

Highest pathogenic variant AF is 9.650926e-7

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CNKSR2	protein_coding	protein_coding	ENST00000379510	22	280278

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000400	123921	2	2	123925	0.0000161

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.61	177	373	0.475	0.0000275	6793
Missense in Polyphen		26	99.306	0.26182		1781
Synonymous	1.52	114	137	0.835	0.0000101	1923
Loss of Function	5.57	3	41.9	0.0717	0.00000346	714

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000401	0.0000401
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000268	0.0000177
Middle Eastern	0.00	0.00
South Asian	0.0000582	0.0000341
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May function as an adapter protein or regulator of Ras signaling pathways. {ECO:0000269|PubMed:14597674}.
• Disease: DISEASE: Mental retardation, X-linked, syndromic, Houge type (MRXSHG) [MIM:301008]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSHG is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. Carrier females may be mildly affected. {ECO:0000269|PubMed:25223753, ECO:0000269|PubMed:28098945}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: EGF-Ncore;MAP2K and MAPK activation;Disease;Signal Transduction;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Signaling by RAS mutants;Signaling by high-kinase activity BRAF mutants;Signaling by moderate kinase activity BRAF mutants;Paradoxical activation of RAF signaling by kinase inactive BRAF;Signaling by BRAF and RAF fusions;Oncogenic MAPK signaling;Diseases of signal transduction (Consensus)

Recessive Scores

• pRec: 0.123

Intolerance Scores

• loftool: 0.369
• rvis_EVS: -0.47
• rvis_percentile_EVS: 23.25

Haploinsufficiency Scores

• pHI: 0.747
• hipred: Y
• hipred_score: 0.785
• ghis: 0.617

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.973

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cnksr2

Gene ontology

• Biological process: regulation of signal transduction;postsynapse organization
• Cellular component: cytoplasm;neuron projection;neuronal cell body;extracellular exosome;glutamatergic synapse;extrinsic component of postsynaptic density membrane
• Molecular function: protein binding;identical protein binding