chr6-45436791-A-G

Variant names:

Variant summary

Our verdict is . The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001024630.4(RUNX2):c.581-1156A>G variant causes a intron change. The variant allele was found at a frequency of 0.49 in 152,038 control chromosomes in the GnomAD database, including 18,610 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.49 ( 18610 hom., cov: 32)

Consequence

RUNX2
NM_001024630.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.17

Publications

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

RUNX2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001024630.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

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	Effect	Exon Rank	Protein	UniProt
RUNX2	NM_001024630.4	MANE Select	c.581-1156A>G	intron	N/A	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1		c.539-1156A>G	intron	N/A	NP_001356334.1	Q13950-2
RUNX2	NM_001015051.4		c.581-1156A>G	intron	N/A	NP_001015051.3	Q13950-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RUNX2	ENST00000647337.2	MANE Select	c.581-1156A>G	intron	N/A	ENSP00000495497.1	Q13950-1
RUNX2	ENST00000359524.7	TSL:1	c.539-1156A>G	intron	N/A	ENSP00000352514.5	Q13950-2
RUNX2	ENST00000625924.1	TSL:1	c.539-1156A>G	intron	N/A	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes

AF:

0.491

AC:

74517

AN:

151920

Hom.:

18599

Cov.:

show subpopulations

Gnomad AFR

AF:

0.394

Gnomad AMI

AF:

0.554

Gnomad AMR

AF:

0.485

Gnomad ASJ

AF:

0.514

Gnomad EAS

AF:

0.613

Gnomad SAS

AF:

0.624

Gnomad FIN

AF:

0.552

Gnomad MID

AF:

0.535

Gnomad NFE

AF:

0.520

Gnomad OTH

AF:

0.504

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.490

AC:

74550

AN:

152038

Hom.:

18610

Cov.:

AF XY:

0.494

AC XY:

36688

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.393

AC:

16299

AN:

41464

American (AMR)

AF:

0.486

AC:

7414

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.514

AC:

1785

AN:

3470

East Asian (EAS)

AF:

0.612

AC:

3162

AN:

5168

South Asian (SAS)

AF:

0.624

AC:

3003

AN:

4812

European-Finnish (FIN)

AF:

0.552

AC:

5827

AN:

10556

Middle Eastern (MID)

AF:

0.531

AC:

156

AN:

294

European-Non Finnish (NFE)

AF:

0.520

AC:

35331

AN:

67986

Other (OTH)

AF:

0.507

AC:

1070

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1971

3942

5913

7884

9855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

686

1372

2058

2744

3430

<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:

0.507

Hom.:

68387

Bravo

AF:

0.480

Asia WGS

AF:

0.598

AC:

2080

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

4.2

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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