rs10992063

Positions:

• chr9-91724406-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.2088C>T​(p.Tyr696=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.45

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=-0.63).
• BP6: Variant 9-91724406-G-A is Benign according to our data. Variant chr9-91724406-G-A is described in ClinVar as [Benign]. Clinvar id is 159815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-91724406-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
ROR2	NM_004560.4	c.2088C>T	p.Tyr696=	synonymous_variant	9/9	ENST00000375708.4	NP_004551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ROR2	ENST00000375708.4	c.2088C>T	p.Tyr696=	synonymous_variant	9/9	1	NM_004560.4	ENSP00000364860	P1
ROR2	ENST00000375715.5	c.1668C>T	p.Tyr556=	synonymous_variant	9/13	1		ENSP00000364867
ROR2	ENST00000550066.5	n.2556C>T		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66573 AN: 151922 Hom.: 14710 Cov.: 33

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

GnomAD3 exomes AF: 0.433 AC: 108721 AN: 251002 Hom.: 24292 AF XY: 0.422 AC XY: 57284 AN XY: 135712

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 SAS exome AF: 0.314

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.: 86 AF XY: 0.429 AC XY: 312248 AN XY: 727160

Gnomad4 AFR exome AF: 0.436

Gnomad4 AMR exome AF: 0.555

Gnomad4 ASJ exome AF: 0.378

Gnomad4 EAS exome AF: 0.445

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.440

Gnomad4 OTH exome AF: 0.420

GnomAD4 genome AF: 0.438 AC: 66585 AN: 152040 Hom.: 14708 Cov.: 33 AF XY: 0.437 AC XY: 32495 AN XY: 74304

Gnomad4 AFR AF: 0.435

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.413

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

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 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	-0.63
CADD	Benign	3.4
DANN	Benign	0.54

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: rs10992063; hg19: chr9-94486688; COSMIC: COSV65216165;