rs2230577

chr9-91724340-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004560.4(ROR2):c.2154C>T(p.Pro718=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,613,426 control chromosomes in the GnomAD database, including 4,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (422 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4461 hom.)
• Consequence: ROR2 NM_004560.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -6.34

Genes affected

ROR2 (HGNC:10257): (receptor tyrosine kinase like orphan receptor 2) The protein encoded by this gene is a receptor protein tyrosine kinase and type I transmembrane protein that belongs to the ROR subfamily of cell surface receptors. The protein may be involved in the early formation of the chondrocytes and may be required for cartilage and growth plate development. Mutations in this gene can cause brachydactyly type B, a skeletal disorder characterized by hypoplasia/aplasia of distal phalanges and nails. In addition, mutations in this gene can cause the autosomal recessive form of Robinow syndrome, which is characterized by skeletal dysplasia with generalized limb bone shortening, segmental defects of the spine, brachydactyly, and a dysmorphic facial appearance. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-91724340-G-A is Benign according to our data. Variant chr9-91724340-G-A is described in ClinVar as [Benign]. Clinvar id is 159816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91724340-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.2154C>T	p.Pro718=	synonymous_variant	9/9	ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.2154C>T	p.Pro718=	synonymous_variant	9/9	1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.1734C>T	p.Pro578=	synonymous_variant	9/13	1
ROR2	ENST00000550066.5	n.2622C>T		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9398 AN: 152180 Hom.: 416 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0766

GnomAD3 exomes AF: 0.0855 AC: 21384 AN: 250022 Hom.: 1108 AF XY: 0.0851 AC XY: 11513 AN XY: 135340

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.0549

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.106

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0661

Gnomad OTH exome AF: 0.0759

GnomAD4 exome AF: 0.0729 AC: 106494 AN: 1461128 Hom.: 4461 Cov.: 91 AF XY: 0.0737 AC XY: 53571 AN XY: 726940

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.0559

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0667

Gnomad4 OTH exome AF: 0.0750

GnomAD4 genome AF: 0.0618 AC: 9415 AN: 152298 Hom.: 422 Cov.: 33 AF XY: 0.0654 AC XY: 4868 AN XY: 74476

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.0939

Gnomad4 ASJ AF: 0.0570

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0664

Gnomad4 OTH AF: 0.0844

Alfa AF: 0.0623 Hom.: 401

Bravo AF: 0.0571

Asia WGS AF: 0.139 AC: 481 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0649

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 10, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2018	- -

Autosomal recessive Robinow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Brachydactyly type B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.034
Dann	Benign	0.60

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: rs2230577; hg19: chr9-94486622;