CNKSR2

protein-coding

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

Gene summary

This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

MANE transcript

NM_014927.5

Inheritance

XL, AD

ClinVar variants

P:62U:285B:47

Top phenotype

Intellectual developmental disorder, X-linked, syndromic, Houge type

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chrX:21,372,801-21,654,695

External References & Databases

Ensembl (ENSG00000149970)

Transcript & Mutation Effects

hg38 • Region Span ~281.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

CNKSR2 was first reported in relation to X-linked complex neurodevelopmental disorder in 2012 (Houge et al. 2012, PMID:22511892). Affected males commonly present with delayed psychomotor development, limited or absent speech, childhood -onset and sleep-related seizures, cognitive deterioration, attention issues, and hyperactivity. Carrier females may be unaffected or mildly affected. To date, at least 17 unique variants predicted to cause loss of function of the protein have been described. In addition to SNVs and indels, whole-gene deletions and intragenic CNVs have also been identified in affected individuals. This gene is intolerant to loss-of function variants (pLI = 1, LOEUF = 0.18, gnomAD v2.1.1). This gene-disease relationship is further supported by expression studies and rescue experiments. In summary, CNKSR2 is definitively associated with X-linked complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 12/16/2020 (SOP Version 8).

intellectual developmental disorder, X-linked, syndromic, Houge typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0030909

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic, Houge typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0030909

Submitter: G2P

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic, Houge typeXL

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 25223753; 28098945

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNKSR2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 172

Inborn genetic diseasesTotal: 64

Intellectual disability, X-linked, syndromic, Houge typeTotal: 64

not specifiedTotal: 42

CNKSR2-related disorderTotal: 19

Intellectual disabilityTotal: 5

Neurodevelopmental disorderTotal: 1

Paediatric disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014927.5. 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			23 clinvar	31 clinvar	2 clinvar	56
missense		3 clinvar	225 clinvar	13 clinvar	1 clinvar	242
nonsense	15 clinvar	9 clinvar	11 clinvar			35
start loss						0
frameshift	14 clinvar	9 clinvar	2 clinvar			25
splice donor/acceptor (+/-2bp)	5 clinvar	7 clinvar	24 clinvar			36
Total	34	28	285	44	3	394

Highest pathogenic variant AF is 9.650926e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014927.5	RefSeq	NP_055742.2	22	MANE Select
ENST00000379510.5	Ensembl	ENSP00000368824.3	22	MANE Select
NM_001168647.3	RefSeq	NP_001162118.1	21	Standard
NM_001168648.3	RefSeq	NP_001162119.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EGF-Ncore
MAP2K and MAPK activation
Disease
Signal Transduction
RAF/MAP kinase cascade

Biological Process

regulation of signal transduction
postsynapse organization

Molecular Function

protein binding
identical protein binding

Cellular Component

cytoplasm
neuron projection
neuronal cell body
extracellular exosome
glutamatergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379510
Coding exons: 22
Length: 280278
Individuals with no LoFs: 123921
Homozygous LoFs: 2
Heterozygous LoFs: 2
Defined: 123925
p: 0.0000161

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.61	177	373	0.475	0.0000275	6793
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000040	0.000030	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000018	rare
South Asian	0.000058	0.000034	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec: 0.123

Intolerance Scores

LoFtool: 0.369
RVIS EVS: -0.47
RVIS percentile EVS: 23.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

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