Genetic Variant RSPO2:p.Arg227Ser (chr8-107901126-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_178565.5(RSPO2):c.681G>C(p.Arg227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RSPO2
NM_178565.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.391

Variant links:

Genes affected

RSPO2 (HGNC:28583): (R-spondin 2) This gene encodes a member of the R-spondin family of proteins. These proteins are secreted ligands of leucine-rich repeat containing G protein-coupled receptors that enhance Wnt signaling through the inhibition of ubiquitin E3 ligases. A chromosomal translocation including this locus that results in the formation of a gene fusion has been identified in multiple human cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

RSPO2 links:

ENSG00000287949 (HGNC:):

ENSG00000287949 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27321023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO2	NM_178565.5 link	c.681G>C	p.Arg227Ser	missense_variant	Exon 6 of 6	ENST00000276659.10	NP_848660.3	Q6UXX9-1B3KVP3
RSPO2	NM_001282863.2 link	c.489G>C	p.Arg163Ser	missense_variant	Exon 5 of 5		NP_001269792.1	Q6UXX9-3
RSPO2	NM_001317942.2 link	c.480G>C	p.Arg160Ser	missense_variant	Exon 5 of 5		NP_001304871.1	Q6UXX9-2B3KVP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO2	ENST00000276659.10 link	c.681G>C	p.Arg227Ser	missense_variant	Exon 6 of 6	1	NM_178565.5	ENSP00000276659.5		Q6UXX9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727218

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.681G>C (p.R227S) alteration is located in exon 6 (coding exon 5) of the RSPO2 gene. This alteration results from a G to C substitution at nucleotide position 681, causing the arginine (R) at amino acid position 227 to be replaced by a serine (S). 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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

.;.;T;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.79

T;T;T;.

M_CAP

Benign

0.045

MetaRNN

Benign

0.27

T;T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.97

.;.;L;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.7

N;N;N;N

REVEL

Uncertain

0.45

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.060

T;D;T;T

Polyphen

0.99, 0.98

.;D;D;.

Vest4

0.42

MutPred

0.17

.;.;Gain of phosphorylation at R227 (P = 0.0205);.;

MVP

0.98

MPC

0.20

ClinPred

0.91

GERP RS

-1.6

Varity_R

0.18

gMVP

0.50

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over