NM_004560.4:c.2154C>T

Variant names:

• chr9-91724340-G-A
• rs2230577
• NM_004560.4:c.2154C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004560.4(ROR2):​c.2154C>T​(p.Pro718Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,613,426 control chromosomes in the GnomAD database, including 4,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (422 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4461 hom.)
• Consequence: ROR2 NM_004560.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -6.34
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-91724340-G-A is Benign according to our data. Variant chr9-91724340-G-A is described in ClinVar as Benign. ClinVar VariationId is 159816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 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.2154C>T	p.Pro718Pro	synonymous	Exon 9 of 9	NP_004551.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROR2	ENST00000375708.4	TSL:1 MANE Select	c.2154C>T	p.Pro718Pro	synonymous	Exon 9 of 9	ENSP00000364860.3	Q01974
	ROR2	ENST00000375715.5	TSL:1	c.1734C>T	p.Pro578Pro	synonymous	Exon 9 of 13	ENSP00000364867.1	B1APY4
	ROR2	ENST00000964760.1		c.2073C>T	p.Pro691Pro	synonymous	Exon 9 of 9	ENSP00000634819.1

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9398 AN: 152180 Hom.: 416 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.0570

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0664

Gnomad OTH AF: 0.0766

GnomAD2 exomes AF: 0.0855 AC: 21384 AN: 250022 AF XY: 0.0851

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.0549

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0661

Gnomad OTH exome AF: 0.0759

GnomAD4 exome AF: 0.0729 AC: 106494 AN: 1461128 Hom.: 4461 Cov.: 91 AF XY: 0.0737 AC XY: 53571 AN XY: 726940

African (AFR) AF: 0.0118 AC: 396 AN: 33480

American (AMR) AF: 0.122 AC: 5452 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 1460 AN: 26136

East Asian (EAS) AF: 0.141 AC: 5583 AN: 39698

South Asian (SAS) AF: 0.107 AC: 9189 AN: 86258

European-Finnish (FIN) AF: 0.102 AC: 5383 AN: 52670

Middle Eastern (MID) AF: 0.0565 AC: 326 AN: 5768

European-Non Finnish (NFE) AF: 0.0667 AC: 74176 AN: 1112008

Other (OTH) AF: 0.0750 AC: 4529 AN: 60388

GnomAD4 genome AF: 0.0618 AC: 9415 AN: 152298 Hom.: 422 Cov.: 33 AF XY: 0.0654 AC XY: 4868 AN XY: 74476

African (AFR) AF: 0.0144 AC: 599 AN: 41570

American (AMR) AF: 0.0939 AC: 1437 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 198 AN: 3472

East Asian (EAS) AF: 0.144 AC: 747 AN: 5176

South Asian (SAS) AF: 0.108 AC: 520 AN: 4832

European-Finnish (FIN) AF: 0.109 AC: 1158 AN: 10614

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0664 AC: 4517 AN: 68008

Other (OTH) AF: 0.0844 AC: 178 AN: 2110

Alfa AF: 0.0624 Hom.: 507

Bravo AF: 0.0571

Asia WGS AF: 0.139 AC: 481 AN: 3478

EpiCase AF: 0.0642

EpiControl AF: 0.0649

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive Robinow syndrome (1)
-	-	1	Brachydactyly type B1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.034
DANN	Benign	0.60
PhyloP100		-6.3
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: rs2230577; hg19: chr9-94486622;