NM_004560.4:c.2088C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004560.4(ROR2):c.2088C>T(p.Tyr696Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.435 in 1,613,784 control chromosomes in the GnomAD database, including 154,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 14708 hom., cov: 33)

Exomes 𝑓: 0.43 ( 139525 hom. )

Consequence

ROR2
NM_004560.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.45

Publications

22 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 9-91724406-G-A is Benign according to our data. Variant chr9-91724406-G-A is described in ClinVar as Benign. ClinVar VariationId is 159815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.45 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.2088C>T	p.Tyr696Tyr	synonymous_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.2088C>T	p.Tyr696Tyr	synonymous_variant	Exon 9 of 9	1	NM_004560.4	ENSP00000364860.3	Q01974
ROR2	ENST00000375715.5 link	c.1668C>T	p.Tyr556Tyr	synonymous_variant	Exon 9 of 13	1		ENSP00000364867.1	B1APY4
ROR2	ENST00000550066.5 link	n.2556C>T		non_coding_transcript_exon_variant	Exon 11 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.438

AC:

66573

AN:

151922

Hom.:

14710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.435

Gnomad AMI

AF:

0.444

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.379

Gnomad EAS

AF:

0.422

Gnomad SAS

AF:

0.301

Gnomad FIN

AF:

0.450

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.440

Gnomad OTH

AF:

0.417

GnomAD2 exomes

AF:

0.433

AC:

108721

AN:

251002

AF XY:

0.422

show subpopulations

Gnomad AFR exome

AF:

0.440

Gnomad AMR exome

AF:

0.557

Gnomad ASJ exome

AF:

0.379

Gnomad EAS exome

AF:

0.401

Gnomad FIN exome

AF:

0.447

Gnomad NFE exome

AF:

0.435

Gnomad OTH exome

AF:

0.420

GnomAD4 exome

AF:

0.434

AC:

634653

AN:

1461744

Hom.:

139525

Cov.:

AF XY:

0.429

AC XY:

312248

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.436

AC:

14583

AN:

33480

American (AMR)

AF:

0.555

AC:

24793

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

9889

AN:

26134

East Asian (EAS)

AF:

0.445

AC:

17654

AN:

39698

South Asian (SAS)

AF:

0.315

AC:

27191

AN:

86256

European-Finnish (FIN)

AF:

0.445

AC:

23762

AN:

53342

Middle Eastern (MID)

AF:

0.318

AC:

1834

AN:

5768

European-Non Finnish (NFE)

AF:

0.440

AC:

489605

AN:

1111968

Other (OTH)

AF:

0.420

AC:

25342

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

27227

54454

81682

108909

136136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14870

29740

44610

59480

74350

<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:

0.438

AC:

66585

AN:

152040

Hom.:

14708

Cov.:

AF XY:

0.437

AC XY:

32495

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.435

AC:

18038

AN:

41484

American (AMR)

AF:

0.499

AC:

7622

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.379

AC:

1314

AN:

3468

East Asian (EAS)

AF:

0.422

AC:

2168

AN:

5138

South Asian (SAS)

AF:

0.300

AC:

1447

AN:

4828

European-Finnish (FIN)

AF:

0.450

AC:

4757

AN:

10578

Middle Eastern (MID)

AF:

0.272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.440

AC:

29881

AN:

67940

Other (OTH)

AF:

0.413

AC:

874

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1955

3910

5865

7820

9775

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.436

Hom.:

8475

Bravo

AF:

0.444

Asia WGS

AF:

0.347

AC:

1205

AN:

3478

EpiCase

AF:

0.425

EpiControl

AF:

0.415

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 14, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive Robinow syndrome

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. -

Brachydactyly type B1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.4

(source)

DANN

Benign

0.54

PhyloP100

2.4

Mutation Taster

=100/0

polymorphism (auto)

(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