8-107901153-C-G

Variant names:

• chr8-107901153-C-G
• rs902694121
• NM_178565.5:c.654G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178565.5(RSPO2):​c.654G>C​(p.Lys218Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RSPO2 NM_178565.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27709162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO2	NM_178565.5	c.654G>C	p.Lys218Asn	missense_variant	Exon 6 of 6	ENST00000276659.10	NP_848660.3
RSPO2	NM_001282863.2	c.462G>C	p.Lys154Asn	missense_variant	Exon 5 of 5		NP_001269792.1
RSPO2	NM_001317942.2	c.453G>C	p.Lys151Asn	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.654G>C	p.Lys218Asn	missense_variant	Exon 6 of 6	1	NM_178565.5	ENSP00000276659.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461740 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727172

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

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

Jul 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.654G>C (p.K218N) 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 654, causing the lysine (K) at amino acid position 218 to be replaced by an asparagine (N). 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	0.38
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.78	T;T;T;.
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.90	.;.;L;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.033	D;D;D;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		1.0, 0.99	.;D;D;.
Vest4		0.34
MutPred		0.15		.;.;Loss of methylation at K218 (P = 0.0152);.;
MVP		0.65
MPC		0.48
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.26
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

LitVar

Other links and lift over

dbSNP: rs902694121; hg19: chr8-108913381;