rs104893992

Positions:

• chr6-45438039-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001024630.4(RUNX2):​c.673C>T​(p.Arg225Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 3.17

Genes affected

RUNX2 (HGNC:10472): (RUNX family transcription factor 2) This gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with an Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Two regions of potential trinucleotide repeat expansions are present in the N-terminal region of the encoded protein, and these and other mutations in this gene have been associated with the bone development disorder cleidocranial dysplasia (CCD). Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternate splicing. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Runt (size 128) in uniprot entity RUNX2_HUMAN there are 37 pathogenic changes around while only 0 benign (100%) in NM_001024630.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 6-45438039-C-T is Pathogenic according to our data. Variant chr6-45438039-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 9303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.673C>T	p.Arg225Trp	missense_variant	5/9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.631C>T	p.Arg211Trp	missense_variant	3/7		NP_001356334.1
RUNX2	NM_001015051.4	c.673C>T	p.Arg225Trp	missense_variant	5/8		NP_001015051.3
RUNX2	NM_001278478.2	c.631C>T	p.Arg211Trp	missense_variant	3/6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.673C>T	p.Arg225Trp	missense_variant	5/9		NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452924 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 723512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cleidocranial dysostosis Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Center of Excellence in Genomics and Precision Dentistry, Faculty of Dentistry, Chulalongkorn University	-	The heterozygous c.673C>T (p.Arg225Trp) in RUNX2 gene was identified in a patient with cleidocranial dysplasia. This variant has been reported in a CCD patient in the former name of RUNX2, CBFA1 (Quack I et. al., 1999). -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with cleidocranial dysplasia (MIM#119600) and metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB; MIM#156510), respectively. MDMHB is caused exclusively by inframe exon duplications (OMIM, PMID: 29891876, PMID: 23290074). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity with intrafamilial variability (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated runt domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. These alternative changes (p.(Arg225Gln), p.(Arg225Leu)) have been reported as pathogenic, and/or observed in individuals with cleidocranial dysplasia (CCD) (ClinVar, PMID: 20702542). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic, and observed in individuals with CCD (ClinVar, PMID: 31548836, PMID: 28738062). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic (ClinVar ID: VCV000009303 ). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 10521292). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000009302, PMID:10545612,19767586). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.935>=0.6, 3CNET: 0.926>=0.75). It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 225 of the RUNX2 protein (p.Arg225Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cleidocranial dysplasia (PMID: 10521292, 31548836). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 9303). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RUNX2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX2 function (PMID: 10521292). This variant disrupts the p.Arg225 amino acid residue in RUNX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10545612, 24222232, 24634175). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;D;D;.;D;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.8	.;D;.;D;D;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;.;D;D;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;D;.
Vest4		0.94
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.88
gMVP		0.97

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: rs104893992; hg19: chr6-45405776;