6-45422681-ACAGCAGCAGCAACAG-ACAGCAGCAGCAACAGCAGCAGCAGCAACAG
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3BS2
The NM_001024630.4(RUNX2):c.174_188dupACAGCAGCAGCAGCA(p.Gln59_Gln63dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000537 in 1,602,436 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000045 ( 0 hom. )
Consequence
RUNX2
NM_001024630.4 disruptive_inframe_insertion
NM_001024630.4 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.06
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 Likely_benign. Variant got -5 ACMG points.
BP3
Nonframeshift variant in repetitive region in NM_001024630.4
BS2
High AC in GnomAd4 at 21 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RUNX2 | NM_001024630.4 | c.174_188dupACAGCAGCAGCAGCA | p.Gln59_Gln63dup | disruptive_inframe_insertion | 3/9 | ENST00000647337.2 | NP_001019801.3 | |
| RUNX2 | NM_001369405.1 | c.132_146dupACAGCAGCAGCAGCA | p.Gln45_Gln49dup | disruptive_inframe_insertion | 1/7 | NP_001356334.1 | ||
| RUNX2 | NM_001015051.4 | c.174_188dupACAGCAGCAGCAGCA | p.Gln59_Gln63dup | disruptive_inframe_insertion | 3/8 | NP_001015051.3 | ||
| RUNX2 | NM_001278478.2 | c.132_146dupACAGCAGCAGCAGCA | p.Gln45_Gln49dup | disruptive_inframe_insertion | 1/6 | NP_001265407.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000132 AC: 20AN: 151444Hom.: 0 Cov.: 30
GnomAD3 genomes
AF:
AC:
20
AN:
151444
Hom.:
Cov.:
30
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000253 AC: 6AN: 236718Hom.: 0 AF XY: 0.0000231 AC XY: 3AN XY: 130112
GnomAD3 exomes
AF:
AC:
6
AN:
236718
Hom.:
AF XY:
AC XY:
3
AN XY:
130112
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000448 AC: 65AN: 1450880Hom.: 0 Cov.: 34 AF XY: 0.0000388 AC XY: 28AN XY: 721650
GnomAD4 exome
AF:
AC:
65
AN:
1450880
Hom.:
Cov.:
34
AF XY:
AC XY:
28
AN XY:
721650
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000139 AC: 21AN: 151556Hom.: 0 Cov.: 30 AF XY: 0.000162 AC XY: 12AN XY: 74064
GnomAD4 genome
AF:
AC:
21
AN:
151556
Hom.:
Cov.:
30
AF XY:
AC XY:
12
AN XY:
74064
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 18, 2024 | This variant, c.174_188dup, results in the insertion of 5 amino acid(s) of the RUNX2 protein (p.Gln67_Gln71dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RUNX2-related conditions. ClinVar contains an entry for this variant (Variation ID: 548496). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 29, 2021 | The RUNX2 c.174_188dup; p.Gln67_Gln71dup variant (rs781355841), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 548496). This variant is found on seven chromosomes (7/267942 alleles) in the Genome Aggregation Database. This variant duplicates five glutamine residues in a polyglutamine tract, leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the p.Gln67_Gln71dup variant is uncertain at this time. - |
Cleidocranial dysostosis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at