Genetic Variant SPRED2:p.Ser286Arg (chr2-65313900-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_181784.3(SPRED2):c.858C>A(p.Ser286Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPRED2
NM_181784.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.578

Variant links:

Genes affected

SPRED2 (HGNC:17722): (sprouty related EVH1 domain containing 2) 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]

SPRED2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10907352).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED2	NM_181784.3 link	c.858C>A	p.Ser286Arg	missense_variant	Exon 6 of 6	ENST00000356388.9	NP_861449.2	Q7Z698-1B3KPL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPRED2	ENST00000356388.9 link	c.858C>A	p.Ser286Arg	missense_variant	Exon 6 of 6	1	NM_181784.3	ENSP00000348753.4	Q7Z698-1
SPRED2	ENST00000452315.5 link	c.903C>A	p.Ser301Arg	missense_variant	Exon 6 of 6	1		ENSP00000390595.1	C9JG63
SPRED2	ENST00000443619.6 link	c.849C>A	p.Ser283Arg	missense_variant	Exon 6 of 6	2		ENSP00000393697.2	Q7Z698-2
SPRED2	ENST00000421087.5 link	c.504C>A	p.Ser168Arg	missense_variant	Exon 3 of 3	3		ENSP00000407627.1	H7C2T4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245376

Hom.:

AF XY:

0.00000749

AC XY:

AN XY:

133528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000895

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457790

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725390

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.858C>A (p.S286R) alteration is located in exon 6 (coding exon 6) of the SPRED2 gene. This alteration results from a C to A substitution at nucleotide position 858, causing the serine (S) at amino acid position 286 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.25

T;.;T;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.1

L;.;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.50

T;T;T;T

Sift4G

Benign

0.51

T;T;.;.

Polyphen

0.20

B;.;.;.

Vest4

0.12

MutPred

0.26

Gain of sheet (P = 0.0028);.;.;.;

MVP

0.84

MPC

0.97

ClinPred

0.041

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over