rs104893995

Variant names:

• chr6-45431945-G-A
• rs104893995
• NM_001024630.4:c.506G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-45431945-G-A
• chr6-45431945-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001024630.4(RUNX2):​c.506G>A​(p.Arg169Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.56
• Publications: 13 publications found

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]

RUNX2 Gene-Disease associations (from GenCC):

• cleidocranial dysplasia 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-45431945-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 9306.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.6033 (below the threshold of 3.09). Trascript score misZ: 1.7818 (below the threshold of 3.09). GenCC associations: The gene is linked to cleidocranial dysplasia 1, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 6-45431945-G-A is Pathogenic according to our data. Variant chr6-45431945-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1698843.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.506G>A	p.Arg169Gln	missense_variant	Exon 4 of 9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.464G>A	p.Arg155Gln	missense_variant	Exon 2 of 7		NP_001356334.1
RUNX2	NM_001015051.4	c.506G>A	p.Arg169Gln	missense_variant	Exon 4 of 8		NP_001015051.3
RUNX2	NM_001278478.2	c.464G>A	p.Arg155Gln	missense_variant	Exon 2 of 6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.506G>A	p.Arg169Gln	missense_variant	Exon 4 of 9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251440 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

RUNX2-related disorder Pathogenic:1

Jul 31, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RUNX2 c.506G>A variant is predicted to result in the amino acid substitution p.Arg169Gln. This variant has been reported to be pathogenic for cleidocranial dysplasia (CCD) (Zhou et al. 1999. PubMedID: 10545612). In addition, two different variants affecting the same amino acid (p.Arg169Phe and Arg169Trp) have been reported in individuals with CCD (Otto et al. 2002. PubMed ID: 11857736; Berkay et al. 2021. PubMed ID: 33987976). At PreventionGenetics. we have observed this variant in two probands underwent RUNX2 sequencing, one of the two probands with personal and family history of CCD. This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Cleidocranial dysostosis Pathogenic:1

Sep 18, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RUNX2 c.506G>A missense variant is classified as LIKELY PATHOGENIC (PM1, PM2, PP3, PP4) The RUNX2 c.506G>A missense variant is a single nucleotide change in exon 4 of the RUNX2 gene, which is predicted to change the amino acid arginine at position 169 in the protein to glutamine. This variant has been reported in a patient with Cleidocranial dysplasia (PMID:10545612). This variant has been reported in dbSNP (rs104893995) but is rare in population databases (gnomAD allele frequency = 0.00040%, 1 het and 0 hom in 251440 sequenced alleles) (PM2). This variant has been reported in HGMD as damaging for Cleidocranial dysplasia (CM992608). It affects an ATP binding consensus motif and is located in the highly conserved runt domain, which is a mutational hot spot (PM1). A different variant affecting the same nucleotide and amino acid (c.506G>C, p.Arg169Pro) has also been identified in patients with Cleidocranial dysplasia. The clinical features of this case are highly specific for Cleidocranial dysplasia, the family history is consistent with the mode of inheritance of this condition and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). Computational predictions support a deleterious effect on the gene or gene product (PP3). -

Cleidocranial dysostosis;C3549874:Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome Pathogenic:1

Jan 31, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 169 of the RUNX2 protein (p.Arg169Gln). This variant is present in population databases (rs104893995, gnomAD 0.003%). This missense change has been observed in individual(s) with cleidocranial dysplasia (PMID: 10545612). ClinVar contains an entry for this variant (Variation ID: 1698843). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RUNX2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg169 amino acid residue in RUNX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 33987976; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	.;D;D;D;.;D;.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;.;.;.
PhyloP100		9.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.7	.;D;.;D;D;.;D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;D;.;D;D;.;D;.
Sift4G	Uncertain	0.0040	D;D;.;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.;D;.
Vest4		0.96
MVP		0.99
MPC		1.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.89
gMVP		0.96
Mutation Taster		=1/99	disease causing

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: rs104893995; hg19: chr6-45399682; COSMIC: COSV61840595;