Genetic Variant SPRED2:p.Val269Leu (chr2-65313953-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_181784.3(SPRED2):c.805G>T(p.Val269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,612,116 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 6 hom. )

Consequence

SPRED2
NM_181784.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.04

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 Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008644044).

BP6

Variant 2-65313953-C-A is Benign according to our data. Variant chr2-65313953-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3770697.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED2	NM_181784.3 link	c.805G>T	p.Val269Leu	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.805G>T	p.Val269Leu	missense_variant	Exon 6 of 6	1	NM_181784.3	ENSP00000348753.4	Q7Z698-1
SPRED2	ENST00000452315.5 link	c.850G>T	p.Val284Leu	missense_variant	Exon 6 of 6	1		ENSP00000390595.1	C9JG63
SPRED2	ENST00000443619.6 link	c.796G>T	p.Val266Leu	missense_variant	Exon 6 of 6	2		ENSP00000393697.2	Q7Z698-2
SPRED2	ENST00000421087.5 link	c.451G>T	p.Val151Leu	missense_variant	Exon 3 of 3	3		ENSP00000407627.1	H7C2T4

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00220

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00152

AC:

378

AN:

247876

Hom.:

AF XY:

0.00153

AC XY:

206

AN XY:

134618

show subpopulations

Gnomad AFR exome

AF:

0.000315

Gnomad AMR exome

AF:

0.000464

Gnomad ASJ exome

AF:

0.000398

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.000984

GnomAD4 exome

AF:

0.00191

AC:

2789

AN:

1459790

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1397

AN XY:

726348

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00444

Gnomad4 NFE exome

AF:

0.00218

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00141

AC:

215

AN:

152326

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

106

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00377

Gnomad4 NFE

AF:

0.00219

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00193

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00169

AC:

205

EpiCase

AF:

0.00174

EpiControl

AF:

0.00261

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPRED2: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.20

T;.;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.7

L;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.28

T;T;T;T

Sift4G

Benign

0.71

T;T;.;.

Polyphen

0.049

B;.;.;.

Vest4

0.37

MutPred

0.078

Gain of phosphorylation at S272 (P = 0.1757);.;.;.;

MVP

0.83

MPC

0.84

ClinPred

0.015

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

Varity_R

0.074

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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