rs11498192

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001024630.4(RUNX2):​c.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC​(p.Ala76_Ala87del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000362 in 1,379,934 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A75A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 29)
Exomes 𝑓: 0.0000036 ( 1 hom. )

Consequence

RUNX2
NM_001024630.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.35

Publications

6 publications found
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]
RUNX2 Gene-Disease associations (from GenCC):
  • cleidocranial dysplasia 1
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
  • metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome
    Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3
Nonframeshift variant in repetitive region in NM_001024630.4
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RUNX2NM_001024630.4 linkc.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC p.Ala76_Ala87del disruptive_inframe_deletion Exon 3 of 9 ENST00000647337.2 NP_001019801.3 Q13950-1
RUNX2NM_001369405.1 linkc.183_218delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC p.Ala62_Ala73del disruptive_inframe_deletion Exon 1 of 7 NP_001356334.1
RUNX2NM_001015051.4 linkc.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC p.Ala76_Ala87del disruptive_inframe_deletion Exon 3 of 8 NP_001015051.3 Q13950-3
RUNX2NM_001278478.2 linkc.183_218delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC p.Ala62_Ala73del disruptive_inframe_deletion Exon 1 of 6 NP_001265407.1 Q32MY8A0A0D9SEN7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RUNX2ENST00000647337.2 linkc.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC p.Ala76_Ala87del disruptive_inframe_deletion Exon 3 of 9 NM_001024630.4 ENSP00000495497.1 Q13950-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD2 exomes
AF:
0.0000246
AC:
4
AN:
162630
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000115
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000134
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000362
AC:
5
AN:
1379934
Hom.:
1
AF XY:
0.00
AC XY:
0
AN XY:
685076
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
28596
American (AMR)
AF:
0.00
AC:
0
AN:
32990
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23584
East Asian (EAS)
AF:
0.0000615
AC:
2
AN:
32500
South Asian (SAS)
AF:
0.0000133
AC:
1
AN:
75430
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
49430
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5326
European-Non Finnish (NFE)
AF:
9.30e-7
AC:
1
AN:
1075584
Other (OTH)
AF:
0.0000177
AC:
1
AN:
56494
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.758
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
29
Alfa
AF:
0.00
Hom.:
134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
4.3
Mutation Taster
=192/8
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs11498192; hg19: chr6-45390486; API