SPRED2

protein-coding

sprouty related EVH1 domain containing 2

Gene summary

SPRED2 is a member of the Sprouty (see SPRY1; MIM 602465)/SPRED family of proteins that regulate growth factor-induced activation of the MAP kinase cascade (see MAPK1; MIM 176948) (Nonami et al., 2004 [PubMed 15465815]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_181784.3

Inheritance

ClinVar variants

P:10U:78B:10

Top phenotype

Noonan syndrome 14

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr2:65,310,851-65,432,637

External References & Databases

Ensembl (ENSG00000198369)

Transcript & Mutation Effects

hg38 • Region Span ~121.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Noonan syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030679

Submitter: G2P

Noonan syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030679

Submitter: Labcorp Genetics (formerly Invitae)

Noonan syndrome 14STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030679

Submitter: PanelApp Australia

Noonan syndrome 14MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030679

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Noonan syndrome 14AR

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Hematologic; Musculoskeletal; Neurologic

Intervention: Cardiovascular; Hematologic; Oncologic

Rationale: Surveillance and treatment related to manifestations such as cardiac anomalies (which include cardiomyopathy and structural anomalies) may be beneficial; The disorder can include bleeding diathesis, and recognition and preventive measures (eg, in surgical situations) may be beneficial

Refs: 34626534

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPRED2 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 81

not providedTotal: 13

Noonan syndrome 14Total: 8

Noonan syndromeTotal: 3

See casesTotal: 2

SPRED2-related conditionTotal: 1

Severe postnatal growth retardationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_181784.3. 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	6 clinvar	1 clinvar	8
missense	1 clinvar		73 clinvar	2 clinvar	1 clinvar	77
nonsense	1 clinvar	2 clinvar				3
start loss						0
frameshift	1 clinvar	5 clinvar	2 clinvar			8
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	3	7	78	8	2	98

Highest pathogenic variant AF is 0.000004337212

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_181784.3	RefSeq	NP_861449.2	6	MANE Select
ENST00000356388.9	Ensembl	ENSP00000348753.4	6	MANE Select
NM_001128210.2	RefSeq	NP_001121682.1	6	Standard
ENST00000421087.5	Ensembl	ENSP00000407627.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Imatinib and Chronic Myeloid Leukemia
Signal Transduction
Signaling by FGFR
Regulation of RAS by GAPs
KitReceptor

Biological Process

inactivation of MAPK activity
multicellular organism development
fibroblast growth factor receptor signaling pathway
negative regulation of peptidyl-threonine phosphorylation
positive regulation of DNA damage response, signal transduction by p53 class mediator

Molecular Function

stem cell factor receptor binding
protein binding
protein kinase binding
protein serine/threonine kinase inhibitor activity

Cellular Component

cytosol
plasma membrane
transport vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356388
Coding exons: 6
Length: 121787
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125748
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.31	234	297	0.787	0.0000210	2752
Missense (PolyPhen)		64	113.38	0.56448		1045
Synonymous	0.966	116	130	0.892	0.0000106	798
Loss of Function	1.33	13	19.3	0.673	0.00000110	203

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00056	0.00055	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00025	0.00025	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negatively regulates Ras signaling pathways and downstream activation of MAP kinases. {ECO:0000269|PubMed:15683364}.;

Recessive Scores

pRec: 0.130

Intolerance Scores

LoFtool: 0.377
RVIS EVS: -0.69
RVIS percentile EVS: 15.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.886

Gene Damage Prediction

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