chr8-107901159-C-G

Variant names:

• chr8-107901159-C-G
• rs1462832583
• NM_178565.5:c.648G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178565.5(RSPO2):​c.648G>C​(p.Arg216Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 0.391

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]

ENSG00000287949 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09014776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO2	NM_178565.5	c.648G>C	p.Arg216Ser	missense_variant	Exon 6 of 6	ENST00000276659.10	NP_848660.3
RSPO2	NM_001282863.2	c.456G>C	p.Arg152Ser	missense_variant	Exon 5 of 5		NP_001269792.1
RSPO2	NM_001317942.2	c.447G>C	p.Arg149Ser	missense_variant	Exon 5 of 5		NP_001304871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO2	ENST00000276659.10	c.648G>C	p.Arg216Ser	missense_variant	Exon 6 of 6	1	NM_178565.5	ENSP00000276659.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.648G>C (p.R216S) 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 648, causing the arginine (R) at amino acid position 216 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	Benign	0.27
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.55	T;T;T;.
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.090	T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.0	.;.;N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.038	D;D;D;D
Sift4G	Benign	0.072	T;T;T;T
Polyphen		0.0080, 0.0040	.;B;B;.
Vest4		0.14
MutPred		0.20		.;.;Gain of phosphorylation at R216 (P = 0.0058);.;
MVP		0.46
MPC		0.16
ClinPred		0.099	T
GERP RS		2.1
Varity_R		0.13
gMVP		0.25

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

Other links and lift over

dbSNP: rs1462832583; hg19: chr8-108913387;