6-45422681-ACAGCAGCAGCAACAGCAGCAGCAGCAACAG-ACAGCAGCAGCAACAGCAGCAGCAGCAACAGCAGCAGCAGCAACAG

Variant summary

Our verdict is Likely benign. The variant received -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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.06

Publications

0 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 GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RUNX2NM_001024630.4 linkc.174_188dupACAGCAGCAGCAGCA p.Gln59_Gln63dup disruptive_inframe_insertion Exon 3 of 9 ENST00000647337.2 NP_001019801.3 Q13950-1
RUNX2NM_001369405.1 linkc.132_146dupACAGCAGCAGCAGCA p.Gln45_Gln49dup disruptive_inframe_insertion Exon 1 of 7 NP_001356334.1
RUNX2NM_001015051.4 linkc.174_188dupACAGCAGCAGCAGCA p.Gln59_Gln63dup disruptive_inframe_insertion Exon 3 of 8 NP_001015051.3 Q13950-3
RUNX2NM_001278478.2 linkc.132_146dupACAGCAGCAGCAGCA p.Gln45_Gln49dup disruptive_inframe_insertion Exon 1 of 6 NP_001265407.1 Q32MY8A0A0D9SEN7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RUNX2ENST00000647337.2 linkc.174_188dupACAGCAGCAGCAGCA p.Gln59_Gln63dup disruptive_inframe_insertion Exon 3 of 9 NM_001024630.4 ENSP00000495497.1 Q13950-1

Frequencies

GnomAD3 genomes
AF:
0.000132
AC:
20
AN:
151444
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000394
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000391
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000191
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000253
AC:
6
AN:
236718
AF XY:
0.0000231
show subpopulations
Gnomad AFR exome
AF:
0.0000732
Gnomad AMR exome
AF:
0.0000614
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000932
Gnomad OTH exome
AF:
0.000351
GnomAD4 exome
AF:
0.0000448
AC:
65
AN:
1450880
Hom.:
0
Cov.:
34
AF XY:
0.0000388
AC XY:
28
AN XY:
721650
show subpopulations
African (AFR)
AF:
0.0000305
AC:
1
AN:
32806
American (AMR)
AF:
0.0000921
AC:
4
AN:
43422
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25900
East Asian (EAS)
AF:
0.000129
AC:
5
AN:
38612
South Asian (SAS)
AF:
0.000106
AC:
9
AN:
84858
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52124
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.0000334
AC:
37
AN:
1107480
Other (OTH)
AF:
0.000150
AC:
9
AN:
59936
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.441
Heterozygous variant carriers
0
3
5
8
10
13
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000139
AC:
21
AN:
151556
Hom.:
0
Cov.:
30
AF XY:
0.000162
AC XY:
12
AN XY:
74064
show subpopulations
African (AFR)
AF:
0.0000724
AC:
3
AN:
41414
American (AMR)
AF:
0.000394
AC:
6
AN:
15234
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3460
East Asian (EAS)
AF:
0.000392
AC:
2
AN:
5100
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4786
European-Finnish (FIN)
AF:
0.000191
AC:
2
AN:
10492
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
290
European-Non Finnish (NFE)
AF:
0.000118
AC:
8
AN:
67782
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Jan 29, 2021
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Jan 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
2.1
Mutation Taster
=71/29
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs781355841; hg19: chr6-45390418; API