chr8-107901109-C-A

Position:

• chr8-107901109-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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.84

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]

(HGNC:):

ACMG classification

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
RSPO2	NM_178565.5	c.698G>T	p.Ser233Ile	missense_variant	6/6	ENST00000276659.10
RSPO2	NM_001282863.2	c.506G>T	p.Ser169Ile	missense_variant	5/5
RSPO2	NM_001317942.2	c.497G>T	p.Ser166Ile	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO2	ENST00000276659.10	c.698G>T	p.Ser233Ile	missense_variant	6/6	1	NM_178565.5	P1
	ENST00000665144.1	n.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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The 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;