rs606231174

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_001024630.4(RUNX2):c.231_260delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC(p.Ala78_Ala87del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000813 in 1,352,972 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 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. A77A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000015 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000074 ( 0 hom. )

Consequence

RUNX2
NM_001024630.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.36

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, Orphanet
metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

RUNX2 links:

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 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX2	NM_001024630.4	MANE Select	c.231_260delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala78_Ala87del	disruptive_inframe_deletion	Exon 3 of 9	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1		c.189_218delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala64_Ala73del	disruptive_inframe_deletion	Exon 1 of 7	NP_001356334.1	Q13950-2
RUNX2	NM_001015051.4		c.231_260delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala78_Ala87del	disruptive_inframe_deletion	Exon 3 of 8	NP_001015051.3	Q13950-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUNX2	ENST00000647337.2	MANE Select	c.231_260delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala78_Ala87del	disruptive_inframe_deletion	Exon 3 of 9	ENSP00000495497.1	Q13950-1
RUNX2	ENST00000359524.7	TSL:1	c.189_218delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala64_Ala73del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000352514.5	Q13950-2
RUNX2	ENST00000625924.1	TSL:1	c.189_218delTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala64_Ala73del	disruptive_inframe_deletion	Exon 1 of 6	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes

AF:

0.0000145

AC:

AN:

137758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000169

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000644

AC:

AN:

155292

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000741

AC:

AN:

1215214

Hom.:

AF XY:

0.00000827

AC XY:

AN XY:

604230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27226

American (AMR)

AF:

0.00

AC:

AN:

27686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20386

East Asian (EAS)

AF:

0.0000326

AC:

AN:

30720

South Asian (SAS)

AF:

0.0000277

AC:

AN:

72204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4722

European-Non Finnish (NFE)

AF:

0.00000640

AC:

AN:

938148

Other (OTH)

AF:

0.00

AC:

AN:

50084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000145

AC:

AN:

137758

Hom.:

Cov.:

AF XY:

0.0000148

AC XY:

AN XY:

67500

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000251

AC:

AN:

39796

American (AMR)

AF:

0.00

AC:

AN:

13776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3066

East Asian (EAS)

AF:

0.00

AC:

AN:

4956

South Asian (SAS)

AF:

0.00

AC:

AN:

4724

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

280

European-Non Finnish (NFE)

AF:

0.0000169

AC:

AN:

59212

Other (OTH)

AF:

0.00

AC:

AN:

1880

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.4

Mutation Taster

=176/24

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over