CNKSR1

protein-coding

connector enhancer of kinase suppressor of Ras 1, the group of Sterile alpha motif domain containing|Pleckstrin homology domain containing|PDZ domain containing

Gene summary

This gene encodes a protein containing several motifs involved in protein-protein interaction, including PDZ, PH (Pleckstrin homology), and SAM (sterile alpha motif) domains. The encoded protein acts as a scaffold component for receptor tyrosine kinase signaling and may mediate crosstalk between different signaling pathways. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

MANE transcript

NM_006314.3

Inheritance

ClinVar variants

P:2U:92B:32

Top phenotype

CNKSR1-related disorder

gnomAD constraint

pLI —, LoF o/e 1

Max pathogenic AF

—

Genomic locus

chr1:26,177,484-26,189,884

External References & Databases

Ensembl (ENSG00000142675)

Transcript & Mutation Effects

hg38 • Region Span ~12.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CNKSR1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 101

not providedTotal: 25

CNKSR1-related disorderTotal: 4

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006314.3. 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			1 clinvar	12 clinvar	3 clinvar	16
missense			85 clinvar	9 clinvar	6 clinvar	100
nonsense		2 clinvar	2 clinvar	1 clinvar		5
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			4 clinvar		1 clinvar	5
Total	0	2	92	22	10	126

Highest pathogenic variant AF is 0.00015171309

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006314.3	RefSeq	NP_006305.2	21	MANE Select
ENST00000361530.11	Ensembl	ENSP00000354609.6	21	MANE Select
NM_001297647.2	RefSeq	NP_001284576.1	21	Standard
NM_001297648.2	RefSeq	NP_001284577.1	13	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

transmembrane receptor protein tyrosine kinase signaling pathway
Ras protein signal transduction
Rho protein signal transduction

Molecular Function

protein binding
protein binding, bridging

Cellular Component

plasma membrane
cell-cell junction
cell cortex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361530
Coding exons: 21
Length: 12484
Individuals with no LoFs: 116638
Homozygous LoFs: 222
Heterozygous LoFs: 8888
Defined: 125748
p: 0.0369

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.569	376	408	0.921	0.0000259	4550
Missense (PolyPhen)		117	130.5	0.89655		1495
Synonymous	0.0271	168	168	0.997	0.0000102	1482
Loss of Function	0.0000730	45	45.0	1.00	0.00000264	456

Population LoF Frequency

Population	CAF	p-value	Status
African	0.025	0.025	notable
Latino/Admixed American	0.015	0.015	notable
Ashkenazi Jewish	0.019	0.019	notable
East Asian	0.0027	0.0027	notable
Finnish	0.041	0.041	notable
European (Non-Finnish)	0.056	0.054	notable
South Asian	0.029	0.028	notable
Other	0.045	0.043	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as an adapter protein or regulator of Ras signaling pathways.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.984
RVIS EVS: 0.52
RVIS percentile EVS: 80.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.814

Gene Damage Prediction

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