chr9-91723689-G-C

Position:

chr9-91723689-G-C

Variant summary

Our verdict is Benign. Variant got -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. 16/21 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 159819.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4, Benign=3}. Variant chr9-91723689-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ROR2	NM_004560.4 link	c.2805C>G	p.Asp935Glu	missense_variant	9/9	ENST00000375708.4	NP_004551.2	Q01974

Ensembl

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

GnomAD3 exomes

AF:

0.00486

AC:

1219

AN:

250668

Hom.:

AF XY:

0.00504

AC XY:

683

AN XY:

135574

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 SAS exome

AF:

0.00493

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

Gnomad4 AFR exome

AF:

0.00116

Gnomad4 AMR exome

AF:

0.000894

Gnomad4 ASJ exome

AF:

0.000498

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00501

Gnomad4 FIN exome

AF:

0.00296

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.00470

GnomAD4 genome

AF:

0.00462

AC:

703

AN:

152312

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00856

Gnomad4 OTH

AF:

0.00189

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2025	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ROR2: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Autosomal recessive Robinow syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 08, 2014	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 17, 2015

- -

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.11

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

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over