rs12683181

chr9-91756046-C-T

Variant summary

Our verdict is Benign. Variant got -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:4
• Conservation: PhyloP100: -0.451

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ROR2	NM_004560.4	c.494+25G>A		intron_variant		ENST00000375708.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ROR2	ENST00000375708.4	c.494+25G>A		intron_variant		1	NM_004560.4	P1
ROR2	ENST00000375715.5	c.74+25G>A		intron_variant		1
ROR2	ENST00000548585.2	n.228G>A		non_coding_transcript_exon_variant	3/3	5
ROR2	ENST00000550066.5	n.962+25G>A		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.669 AC: 168073 AN: 251288 Hom.: 57461 AF XY: 0.678 AC XY: 92137 AN XY: 135816

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 SAS exome AF: 0.705

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

Gnomad4 AFR exome AF: 0.637

Gnomad4 AMR exome AF: 0.530

Gnomad4 ASJ exome AF: 0.693

Gnomad4 EAS exome AF: 0.467

Gnomad4 SAS exome AF: 0.706

Gnomad4 FIN exome AF: 0.699

Gnomad4 NFE exome AF: 0.738

Gnomad4 OTH exome AF: 0.706

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

Gnomad4 AFR AF: 0.641

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.686

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.698

Gnomad4 FIN AF: 0.705

Gnomad4 NFE AF: 0.739

Gnomad4 OTH AF: 0.654

Alfa AF: 0.720 Hom.: 10424

Bravo AF: 0.671

Asia WGS AF: 0.577 AC: 2007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Autosomal recessive Robinow syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Brachydactyly type B1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.66
Dann	Benign	0.80

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