rs104893995

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate PP5_Moderate

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 Pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.56

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 10 ACMG points.

• PS1: Transcript NM_001024630.4 (RUNX2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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
• 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 [Pathogenic]. Clinvar id is 1698843.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.506G>A	p.Arg169Gln	missense_variant	4/9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135892

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RUNX2-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Sep 18, 2020

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 31, 2024

- -

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;.;.;.
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

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