chr8-107901107-C-T

Position:

• chr8-107901107-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178565.5(RSPO2):​c.700G>A​(p.Val234Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: RSPO2 NM_178565.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.10

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02854541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO2	NM_178565.5	c.700G>A	p.Val234Ile	missense_variant	6/6	ENST00000276659.10
RSPO2	NM_001282863.2	c.508G>A	p.Val170Ile	missense_variant	5/5
RSPO2	NM_001317942.2	c.499G>A	p.Val167Ile	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO2	ENST00000276659.10	c.700G>A	p.Val234Ile	missense_variant	6/6	1	NM_178565.5	P1
	ENST00000665144.1	n.81-17063C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000260 AC: 65 AN: 249910 Hom.: 0 AF XY: 0.000229 AC XY: 31 AN XY: 135210

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000165 AC: 241 AN: 1461832 Hom.: 1 Cov.: 30 AF XY: 0.000161 AC XY: 117 AN XY: 727220

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000381

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152296 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74474

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000306

ExAC AF: 0.000173 AC: 21

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 234 of the RSPO2 protein (p.Val234Ile). This variant is present in population databases (rs761237646, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with RSPO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2067591). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.23
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T;T;T;.
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.029	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.95	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.28	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	0.94	T;T;T;T
Polyphen		0.0030	.;B;B;.
Vest4		0.10
MVP		0.32
MPC		0.11
ClinPred		0.017	T
GERP RS		6.0
Varity_R		0.043
gMVP		0.089

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: rs761237646; hg19: chr8-108913335; COSMIC: COSV99409618;