rs1554384228
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2
The NM_001024630.4(RUNX2):c.217del(p.Ala73ArgfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,531,060 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 29)
Exomes 𝑓: 0.0000043 ( 1 hom. )
Consequence
RUNX2
NM_001024630.4 frameshift
NM_001024630.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.995
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 Uncertain_significance. Variant got 5 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 6-45422749-AG-A is Pathogenic according to our data. Variant chr6-45422749-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548612.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
BS2
?
High AC in GnomAdExome4 at 6 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RUNX2 | NM_001024630.4 | c.217del | p.Ala73ArgfsTer71 | frameshift_variant | 3/9 | ENST00000647337.2 | |
RUNX2 | NM_001369405.1 | c.175del | p.Ala59ArgfsTer71 | frameshift_variant | 1/7 | ||
RUNX2 | NM_001015051.4 | c.217del | p.Ala73ArgfsTer71 | frameshift_variant | 3/8 | ||
RUNX2 | NM_001278478.2 | c.175del | p.Ala59ArgfsTer71 | frameshift_variant | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RUNX2 | ENST00000647337.2 | c.217del | p.Ala73ArgfsTer71 | frameshift_variant | 3/9 | NM_001024630.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000661 AC: 1AN: 151186Hom.: 0 Cov.: 29
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GnomAD4 exome AF: 0.00000435 AC: 6AN: 1379874Hom.: 1 Cov.: 33 AF XY: 0.00000146 AC XY: 1AN XY: 685050
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
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
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at