6-45422767-C-CAGGA
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PVS1PM2BS2
The NM_001024630.4(RUNX2):c.233_234insAGGA(p.Ala79GlyfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,106,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000045 ( 0 hom. )
Consequence
RUNX2
NM_001024630.4 frameshift
NM_001024630.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.250
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
BS2
High AC in GnomAdExome4 at 5 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RUNX2 | NM_001024630.4 | c.233_234insAGGA | p.Ala79GlyfsTer83 | frameshift_variant | Exon 3 of 9 | ENST00000647337.2 | NP_001019801.3 | |
| RUNX2 | NM_001369405.1 | c.191_192insAGGA | p.Ala65GlyfsTer83 | frameshift_variant | Exon 1 of 7 | NP_001356334.1 | ||
| RUNX2 | NM_001015051.4 | c.233_234insAGGA | p.Ala79GlyfsTer83 | frameshift_variant | Exon 3 of 8 | NP_001015051.3 | ||
| RUNX2 | NM_001278478.2 | c.191_192insAGGA | p.Ala65GlyfsTer83 | frameshift_variant | Exon 1 of 6 | NP_001265407.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
29
GnomAD4 exome AF: 0.00000452 AC: 5AN: 1106248Hom.: 0 Cov.: 34 AF XY: 0.00000184 AC XY: 1AN XY: 544400
GnomAD4 exome
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34
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GnomAD4 genome
GnomAD4 genome
Cov.:
29
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Cleidocranial dysostosis Uncertain:1
Mar 05, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome Uncertain:1
Mar 05, 2018
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at