9-91723689-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004560.4(ROR2):c.2805C>G(p.Asp935Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00803 in 1,613,804 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0046 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 79 hom. )

Consequence

ROR2
NM_004560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: -1.58

Publications

13 publications found

Variant links:

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]

ROR2 Gene-Disease associations (from GenCC):

brachydactyly type B1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
autosomal recessive Robinow syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ROR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004309505).

BP6

Variant 9-91723689-G-C is Benign according to our data. Variant chr9-91723689-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159819.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00462 (703/152312) while in subpopulation NFE AF = 0.00856 (582/68022). AF 95% confidence interval is 0.00798. There are 2 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.2805C>G	p.Asp935Glu	missense_variant	Exon 9 of 9	ENST00000375708.4	NP_004551.2	Q01974

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ROR2	ENST00000375708.4 link	c.2805C>G	p.Asp935Glu	missense_variant	Exon 9 of 9	1	NM_004560.4	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5 link	c.1920+465C>G		intron_variant	Intron 9 of 12	1		ENSP00000364867.1	B1APY4
ROR2	ENST00000550066.5 link	n.3273C>G		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

703

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00856

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00486

AC:

1219

AN:

250668

AF XY:

0.00504

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00252

Gnomad NFE exome

AF:

0.00829

Gnomad OTH exome

AF:

0.00360

GnomAD4 exome

AF:

0.00839

AC:

12256

AN:

1461492

Hom.:

Cov.:

AF XY:

0.00827

AC XY:

6015

AN XY:

727030

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33478

American (AMR)

AF:

0.000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000498

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00501

AC:

432

AN:

86248

European-Finnish (FIN)

AF:

0.00296

AC:

157

AN:

53128

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0102

AC:

11288

AN:

1111940

Other (OTH)

AF:

0.00470

AC:

284

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

747

1494

2241

2988

3735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

444

888

1332

1776

2220

<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

AF:

0.00462

AC:

703

AN:

152312

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

41570

American (AMR)

AF:

0.000784

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00269

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00856

AC:

582

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00635

Hom.:

Bravo

AF:

0.00436

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00491

AC:

596

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00742

EpiControl

AF:

0.00676

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:6

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ROR2: BP4, BS1, BS2 -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive Robinow syndrome

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jul 08, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 17, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brachydactyly type B1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.11

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.11

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.59

M_CAP

Benign

0.019

MetaRNN

Benign

0.0043

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-1.6

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.070

REVEL

Benign

0.17

Sift

Benign

0.47

Sift4G

Benign

0.83

Polyphen

0.0

Vest4

0.12

MutPred

0.049

Loss of loop (P = 0.0073);

MVP

0.47

MPC

0.19

ClinPred

0.0043

GERP RS

-5.5

Varity_R

0.033

gMVP

0.055

Mutation Taster

=98/2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over