rs104893995
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PP3_ModeratePP5_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
Consequence
NM_001024630.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
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: 1AN: 251440Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at