chr8-107997664-A-G

Variant names:

• chr8-107997664-A-G
• rs1348470
• NM_178565.5:c.95-8420T>C

Variant summary

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

The NM_178565.5(RSPO2):​c.95-8420T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0304 in 152,308 control chromosomes in the GnomAD database, including 195 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 0.030 (195 hom., cov: 33)
• Consequence: RSPO2 NM_178565.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.41
• Publications: 0 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178565.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO2	NM_178565.5	MANE Select	c.95-8420T>C		intron	N/A	NP_848660.3
	RSPO2	NM_001282863.2		c.95-36847T>C		intron	N/A	NP_001269792.1
	RSPO2	NM_001317942.2		c.-107-8420T>C		intron	N/A	NP_001304871.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO2	ENST00000276659.10	TSL:1 MANE Select	c.95-8420T>C		intron	N/A	ENSP00000276659.5
	RSPO2	ENST00000517781.5	TSL:1	c.95-36847T>C		intron	N/A	ENSP00000427937.1
	RSPO2	ENST00000517939.5	TSL:1	c.-107-8420T>C		intron	N/A	ENSP00000428940.1

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4612 AN: 152192 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0923

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.0679

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.0229

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

GnomAD4 genome AF: 0.0304 AC: 4630 AN: 152308 Hom.: 195 Cov.: 33 AF XY: 0.0307 AC XY: 2289 AN XY: 74484

African (AFR) AF: 0.0924 AC: 3840 AN: 41562

American (AMR) AF: 0.0145 AC: 222 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3470

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5184

South Asian (SAS) AF: 0.0684 AC: 330 AN: 4824

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10628

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68008

Other (OTH) AF: 0.0241 AC: 51 AN: 2116

Alfa AF: 0.0170 Hom.: 7

Bravo AF: 0.0339

Asia WGS AF: 0.0520 AC: 180 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.012
DANN	Benign	0.44
PhyloP100		-2.4
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: rs1348470; hg19: chr8-109009892;