8-108042440-C-T

Variant names:

• chr8-108042440-C-T
• rs16877095
• NM_178565.5:c.94+40105G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_178565.5(RSPO2):​c.94+40105G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 152,054 control chromosomes in the GnomAD database, including 1,352 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1352 hom., cov: 31)
• Consequence: RSPO2 NM_178565.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• Publications: 6 publications found

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]

RSPO2 Gene-Disease associations (from GenCC):

• tetraamelia syndrome 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• tetraamelia-multiple malformations syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO2	NM_178565.5	c.94+40105G>A		intron_variant	Intron 2 of 5	ENST00000276659.10	NP_848660.3
RSPO2	NM_001282863.2	c.94+40105G>A		intron_variant	Intron 2 of 4		NP_001269792.1
RSPO2	NM_001317942.2	c.-108+39427G>A		intron_variant	Intron 1 of 4		NP_001304871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO2	ENST00000276659.10	c.94+40105G>A		intron_variant	Intron 2 of 5	1	NM_178565.5	ENSP00000276659.5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17778 AN: 151936 Hom.: 1342 Cov.: 31

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.199

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.108

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.117 AC: 17797 AN: 152054 Hom.: 1352 Cov.: 31 AF XY: 0.119 AC XY: 8870 AN XY: 74322

African (AFR) AF: 0.0305 AC: 1266 AN: 41500

American (AMR) AF: 0.0902 AC: 1376 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1440 AN: 5164

South Asian (SAS) AF: 0.198 AC: 955 AN: 4812

European-Finnish (FIN) AF: 0.156 AC: 1647 AN: 10552

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10349 AN: 67980

Other (OTH) AF: 0.116 AC: 245 AN: 2110

Alfa AF: 0.126 Hom.: 2685

Bravo AF: 0.108

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.50
PhyloP100		0.026
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16877095; hg19: chr8-109054668;