Genetic Variant RSPO2:p.Glu137Lys (chr8-107960692-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.96

Publications

0 publications found

Variant links:

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

RSPO2 links:

ENSG00000287949 (HGNC:):

ENSG00000287949 links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSPO2	NM_178565.5 link	c.409G>A	p.Glu137Lys	missense_variant	Exon 4 of 6	ENST00000276659.10	NP_848660.3	Q6UXX9-1B3KVP3
RSPO2	NM_001282863.2 link	c.220G>A	p.Glu74Lys	missense_variant	Exon 3 of 5		NP_001269792.1	Q6UXX9-3
RSPO2	NM_001317942.2 link	c.208G>A	p.Glu70Lys	missense_variant	Exon 3 of 5		NP_001304871.1	Q6UXX9-2B3KVP3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSPO2	ENST00000276659.10 link	c.409G>A	p.Glu137Lys	missense_variant	Exon 4 of 6	1	NM_178565.5	ENSP00000276659.5		Q6UXX9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460008

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44414

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

85498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111466

Other (OTH)

AF:

0.00

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.24

.;.;T;.;.

Eigen

Benign

-0.0086

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D;.;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.54

.;.;N;.;.

PhyloP100

5.0

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.62

N;N;N;N;N

REVEL

Benign

0.27

Sift

Benign

0.68

T;T;T;T;T

Sift4G

Benign

0.60

T;T;T;T;T

Polyphen

0.0090, 0.59

.;B;P;.;.

Vest4

0.57

MutPred

0.40

.;.;Gain of ubiquitination at E137 (P = 0.0109);.;.;

MVP

0.17

MPC

0.16

ClinPred

0.66

GERP RS

5.0

Varity_R

0.23

gMVP

0.39

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over