8-107901109-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_178565.5(RSPO2):​c.698G>T​(p.Ser233Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S233G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

RSPO2
NM_178565.5 missense

Scores

2
13
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RSPO2NM_178565.5 linkuse as main transcriptc.698G>T p.Ser233Ile missense_variant 6/6 ENST00000276659.10
RSPO2NM_001282863.2 linkuse as main transcriptc.506G>T p.Ser169Ile missense_variant 5/5
RSPO2NM_001317942.2 linkuse as main transcriptc.497G>T p.Ser166Ile missense_variant 5/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RSPO2ENST00000276659.10 linkuse as main transcriptc.698G>T p.Ser233Ile missense_variant 6/61 NM_178565.5 P1Q6UXX9-1
ENST00000665144.1 linkuse as main transcriptn.81-17061C>A intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

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 submitterclinical testingAmbry GeneticsFeb 15, 2023The c.698G>T (p.S233I) alteration is located in exon 6 (coding exon 5) of the RSPO2 gene. This alteration results from a G to T substitution at nucleotide position 698, causing the serine (S) at amino acid position 233 to be replaced by an isoleucine (I). 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
0.19
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.23
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
.;.;T;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.90
D;D;D;.
M_CAP
Uncertain
0.092
D
MetaRNN
Uncertain
0.50
D;D;D;D
MetaSVM
Uncertain
0.0046
D
MutationAssessor
Benign
0.97
.;.;L;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-2.4
N;D;N;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.0020
D;D;D;D
Sift4G
Uncertain
0.058
T;D;T;D
Polyphen
1.0, 0.99
.;D;D;.
Vest4
0.61
MutPred
0.24
.;.;Loss of phosphorylation at S233 (P = 0.0697);.;
MVP
0.78
MPC
0.66
ClinPred
0.97
D
GERP RS
6.0
Varity_R
0.54
gMVP
0.52

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.

Other links and lift over

hg19: chr8-108913337; COSMIC: COSV99410522; API