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

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RUNX2
NM_001024630.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.56
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
RUNX2NM_001024630.4 linkuse as main transcriptc.506G>A p.Arg169Gln missense_variant 4/9 ENST00000647337.2 NP_001019801.3 Q13950-1
RUNX2NM_001369405.1 linkuse as main transcriptc.464G>A p.Arg155Gln missense_variant 2/7 NP_001356334.1
RUNX2NM_001015051.4 linkuse as main transcriptc.506G>A p.Arg169Gln missense_variant 4/8 NP_001015051.3 Q13950-3
RUNX2NM_001278478.2 linkuse as main transcriptc.464G>A p.Arg155Gln missense_variant 2/6 NP_001265407.1 Q32MY8A0A0D9SEN7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RUNX2ENST00000647337.2 linkuse as main transcriptc.506G>A p.Arg169Gln missense_variant 4/9 NM_001024630.4 ENSP00000495497.1 Q13950-1

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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

RUNX2-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 31, 2024The 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 submitterclinical testingGenetics and Molecular Pathology, SA PathologySep 18, 2020The 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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