chr8-107958139-A-G

Position:

• chr8-107958139-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178565.5(RSPO2):​c.557T>C​(p.Leu186Pro) variant causes a missense change. The variant allele was found at a frequency of 0.603 in 1,612,650 control chromosomes in the GnomAD database, including 302,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.49 (21481 hom., cov: 31)
  • Exomes 𝑓: 0.61 (280539 hom.)
• Consequence: RSPO2 NM_178565.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.75

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6289185E-5).
• BP6: Variant 8-107958139-A-G is Benign according to our data. Variant chr8-107958139-A-G is described in ClinVar as [Benign]. Clinvar id is 1280490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RSPO2	NM_178565.5	c.557T>C	p.Leu186Pro	missense_variant	5/6	ENST00000276659.10
RSPO2	NM_001282863.2	c.365T>C	p.Leu122Pro	missense_variant	4/5
RSPO2	NM_001317942.2	c.356T>C	p.Leu119Pro	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RSPO2	ENST00000276659.10	c.557T>C	p.Leu186Pro	missense_variant	5/6	1	NM_178565.5	P1
	ENST00000665144.1	n.326-1071A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.490 AC: 74447 AN: 151842 Hom.: 21485 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.572

Gnomad ASJ AF: 0.590

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.594

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.540

GnomAD3 exomes AF: 0.588 AC: 147504 AN: 251070 Hom.: 45297 AF XY: 0.595 AC XY: 80764 AN XY: 135692

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.688

Gnomad SAS exome AF: 0.601

Gnomad FIN exome AF: 0.590

Gnomad NFE exome AF: 0.623

Gnomad OTH exome AF: 0.609

GnomAD4 exome AF: 0.615 AC: 897658 AN: 1460692 Hom.: 280539 Cov.: 40 AF XY: 0.615 AC XY: 446721 AN XY: 726706

Gnomad4 AFR exome AF: 0.145

Gnomad4 AMR exome AF: 0.602

Gnomad4 ASJ exome AF: 0.586

Gnomad4 EAS exome AF: 0.671

Gnomad4 SAS exome AF: 0.601

Gnomad4 FIN exome AF: 0.594

Gnomad4 NFE exome AF: 0.630

Gnomad4 OTH exome AF: 0.607

GnomAD4 genome AF: 0.490 AC: 74456 AN: 151958 Hom.: 21481 Cov.: 31 AF XY: 0.492 AC XY: 36548 AN XY: 74252

Gnomad4 AFR AF: 0.158

Gnomad4 AMR AF: 0.573

Gnomad4 ASJ AF: 0.590

Gnomad4 EAS AF: 0.693

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.594

Gnomad4 NFE AF: 0.626

Gnomad4 OTH AF: 0.538

Alfa AF: 0.603 Hom.: 71163

Bravo AF: 0.478

TwinsUK AF: 0.630 AC: 2335

ALSPAC AF: 0.626 AC: 2413

ESP6500AA AF: 0.174 AC: 765

ESP6500EA AF: 0.626 AC: 5385

ExAC AF: 0.578 AC: 70194

Asia WGS AF: 0.589 AC: 2044 AN: 3478

EpiCase AF: 0.636

EpiControl AF: 0.624

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Humerofemoral hypoplasia with radiotibial ray deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Tetraamelia syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Benign	0.91
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.42	T;T;T;.
MetaRNN	Benign	0.000016	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.0029	P;P;P;P
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.66	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.032
MPC		0.22
ClinPred		0.0084	T
GERP RS		5.0
Varity_R		0.19
gMVP		0.51

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: rs601558; hg19: chr8-108970367; COSMIC: COSV52647922; COSMIC: COSV52647922;