Variant 2-65314030-G-A 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.728C>T(p.Pro243Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,128 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

SPRED2
NM_181784.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16

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=0.033880174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPRED2	NM_181784.3 linkuse as main transcript	c.728C>T	p.Pro243Leu	missense_variant	6/6	ENST00000356388.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPRED2	ENST00000356388.9 linkuse as main transcript	c.728C>T	p.Pro243Leu	missense_variant	6/6	1	NM_181784.3	P4	Q7Z698-1
SPRED2	ENST00000452315.5 linkuse as main transcript	c.773C>T	p.Pro258Leu	missense_variant	6/6	1
SPRED2	ENST00000443619.6 linkuse as main transcript	c.719C>T	p.Pro240Leu	missense_variant	6/6	2		A1	Q7Z698-2
SPRED2	ENST00000421087.5 linkuse as main transcript	c.374C>T	p.Pro125Leu	missense_variant	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250546

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.000433

Gnomad AMR exome

AF:

0.0000289

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:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461800

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000288

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000131

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000117

ExAC

AF:

0.0000412

AC:

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

Jan 04, 2024

The c.728C>T (p.P243L) alteration is located in exon 6 (coding exon 6) of the SPRED2 gene. This alteration results from a C to T substitution at nucleotide position 728, causing the proline (P) at amino acid position 243 to be replaced by a leucine (L). 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

0.064

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.17

T;.;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.89

D;D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.0

L;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.35

T;T;.;.

Polyphen

0.0070

B;.;.;.

Vest4

0.079

MVP

0.85

MPC

0.87

ClinPred

0.033

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.59

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