8-107960692-C-T

Variant names:

• chr8-107960692-C-T
• rs1554576888
• NM_178565.5:c.409G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178565.5(RSPO2):​c.409G>A​(p.Glu137Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RSPO2 NM_178565.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• tetraamelia-multiple malformations syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000287949 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.202977).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO2	NM_178565.5	MANE Select	c.409G>A	p.Glu137Lys	missense	Exon 4 of 6	NP_848660.3
	RSPO2	NM_001282863.2		c.220G>A	p.Glu74Lys	missense	Exon 3 of 5	NP_001269792.1	Q6UXX9-3
	RSPO2	NM_001317942.2		c.208G>A	p.Glu70Lys	missense	Exon 3 of 5	NP_001304871.1	Q6UXX9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RSPO2	ENST00000276659.10	TSL:1 MANE Select	c.409G>A	p.Glu137Lys	missense	Exon 4 of 6	ENSP00000276659.5	Q6UXX9-1
	RSPO2	ENST00000517781.5	TSL:1	c.220G>A	p.Glu74Lys	missense	Exon 3 of 5	ENSP00000427937.1	Q6UXX9-3
	RSPO2	ENST00000517939.5	TSL:1	c.208G>A	p.Glu70Lys	missense	Exon 3 of 5	ENSP00000428940.1	Q6UXX9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460008 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726128

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.00 AC: 0 AN: 85498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111466

Other (OTH) AF: 0.00 AC: 0 AN: 60338

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.0086
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.54	N
PhyloP100		5.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.27
Sift	Benign	0.68	T
Sift4G	Benign	0.60	T
Polyphen		0.0090	B
Vest4		0.57
MutPred		0.40		Gain of ubiquitination at E137 (P = 0.0109)
MVP		0.17
MPC		0.16
ClinPred		0.66	D
GERP RS		5.0
Varity_R		0.23
gMVP		0.39
Mutation Taster		=71/29	polymorphism

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: rs1554576888; hg19: chr8-108972920;