Variant 2-65313910-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_181784.3(SPRED2):c.848G>A(p.Arg283His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,610,502 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00033 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00028 ( 0 hom. )

Consequence

SPRED2
NM_181784.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.31

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010616392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPRED2	NM_181784.3 linkuse as main transcript	c.848G>A	p.Arg283His	missense_variant	6/6	ENST00000356388.9	NP_861449.2	Q7Z698-1B3KPL5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPRED2	ENST00000356388.9 linkuse as main transcript	c.848G>A	p.Arg283His	missense_variant	6/6	1	NM_181784.3	ENSP00000348753.4	Q7Z698-1
SPRED2	ENST00000452315.5 linkuse as main transcript	c.893G>A	p.Arg298His	missense_variant	6/6	1		ENSP00000390595.1	C9JG63
SPRED2	ENST00000443619.6 linkuse as main transcript	c.839G>A	p.Arg280His	missense_variant	6/6	2		ENSP00000393697.2	Q7Z698-2
SPRED2	ENST00000421087.5 linkuse as main transcript	c.494G>A	p.Arg165His	missense_variant	3/3	3		ENSP00000407627.1	H7C2T4

Frequencies

GnomAD3 genomes

AF:

0.000328

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000358

AC:

AN:

245748

Hom.:

AF XY:

0.000374

AC XY:

AN XY:

133730

show subpopulations

Gnomad AFR exome

AF:

0.0000638

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00310

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000322

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000285

AC:

415

AN:

1458158

Hom.:

Cov.:

AF XY:

0.000265

AC XY:

192

AN XY:

725592

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000447

Gnomad4 ASJ exome

AF:

0.00390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000228

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000328

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000475

Hom.:

Bravo

AF:

0.000438

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.848G>A (p.R283H) alteration is located in exon 6 (coding exon 6) of the SPRED2 gene. This alteration results from a G to A substitution at nucleotide position 848, causing the arginine (R) at amino acid position 283 to be replaced by a histidine (H). 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

0.073

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.0

N;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.71

N;N;N;N

REVEL

Benign

0.11

Sift

Benign

0.13

T;T;T;T

Sift4G

Benign

0.14

T;T;.;.

Polyphen

0.0

B;.;.;.

Vest4

0.044

MVP

0.87

MPC

1.0

ClinPred

0.026

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.068

gMVP

0.27

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