rs12683181

Variant names:

• chr9-91756046-C-T
• rs12683181
• NM_004560.4:c.494+25G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004560.4(ROR2):​c.494+25G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 1,609,944 control chromosomes in the GnomAD database, including 413,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35975 hom., cov: 33)
  • Exomes 𝑓: 0.72 (377446 hom.)
• Consequence: ROR2 NM_004560.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.451
• Publications: 13 publications found

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), PanelApp Australia
• autosomal recessive Robinow syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 9-91756046-C-T is Benign according to our data. Variant chr9-91756046-C-T is described in ClinVar as Benign. ClinVar VariationId is 259431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004560.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	NM_004560.4	MANE Select	c.494+25G>A		intron	N/A	NP_004551.2
	ROR2	NM_001318204.2		c.494+25G>A		intron	N/A	NP_001305133.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.494+25G>A		intron	N/A	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.74+25G>A		intron	N/A	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.494+25G>A		intron	N/A	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.684 AC: 104039 AN: 152030 Hom.: 35952 Cov.: 33

Gnomad AFR AF: 0.641

Gnomad AMI AF: 0.704

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.686

Gnomad EAS AF: 0.481

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.658

GnomAD2 exomes AF: 0.669 AC: 168073 AN: 251288 AF XY: 0.678

Gnomad AFR exome AF: 0.633

Gnomad AMR exome AF: 0.513

Gnomad ASJ exome AF: 0.692

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.734

Gnomad OTH exome AF: 0.693

GnomAD4 exome AF: 0.717 AC: 1044840 AN: 1457796 Hom.: 377446 Cov.: 35 AF XY: 0.718 AC XY: 520797 AN XY: 725564

African (AFR) AF: 0.637 AC: 21236 AN: 33354

American (AMR) AF: 0.530 AC: 23682 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 18094 AN: 26110

East Asian (EAS) AF: 0.467 AC: 18527 AN: 39680

South Asian (SAS) AF: 0.706 AC: 60817 AN: 86180

European-Finnish (FIN) AF: 0.699 AC: 37334 AN: 53408

Middle Eastern (MID) AF: 0.712 AC: 4104 AN: 5764

European-Non Finnish (NFE) AF: 0.738 AC: 818496 AN: 1108346

Other (OTH) AF: 0.706 AC: 42550 AN: 60244

GnomAD4 genome AF: 0.684 AC: 104107 AN: 152148 Hom.: 35975 Cov.: 33 AF XY: 0.680 AC XY: 50559 AN XY: 74360

African (AFR) AF: 0.641 AC: 26592 AN: 41474

American (AMR) AF: 0.612 AC: 9355 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.686 AC: 2381 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2488 AN: 5176

South Asian (SAS) AF: 0.698 AC: 3363 AN: 4816

European-Finnish (FIN) AF: 0.705 AC: 7460 AN: 10586

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.739 AC: 50258 AN: 68018

Other (OTH) AF: 0.654 AC: 1378 AN: 2108

Alfa AF: 0.720 Hom.: 10424

Bravo AF: 0.671

Asia WGS AF: 0.577 AC: 2007 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive Robinow syndrome (1)
-	-	1	Brachydactyly type B1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.66
DANN	Benign	0.80
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12683181; hg19: chr9-94518328; COSMIC: COSV65216597; COSMIC: COSV65216597;