rs3749864

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001024630.4(RUNX2):c.423+39G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 1,591,676 control chromosomes in the GnomAD database, including 8,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 714 hom., cov: 31)

Exomes 𝑓: 0.10 ( 8142 hom. )

Consequence

RUNX2
NM_001024630.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.45

Publications

1 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 6-45422996-G-C is Benign according to our data. Variant chr6-45422996-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 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.423+39G>C	intron	N/A	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1		c.381+39G>C	intron	N/A	NP_001356334.1	Q13950-2
RUNX2	NM_001015051.4		c.423+39G>C	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.423+39G>C	intron	N/A	ENSP00000495497.1	Q13950-1
RUNX2	ENST00000359524.7	TSL:1	c.381+39G>C	intron	N/A	ENSP00000352514.5	Q13950-2
RUNX2	ENST00000625924.1	TSL:1	c.381+39G>C	intron	N/A	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes

AF:

0.0800

AC:

12138

AN:

151802

Hom.:

717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0830

Gnomad ASJ

AF:

0.0513

Gnomad EAS

AF:

0.0545

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.0987

Gnomad NFE

AF:

0.0978

Gnomad OTH

AF:

0.0699

GnomAD2 exomes

AF:

0.102

AC:

21368

AN:

210156

AF XY:

0.108

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.0690

Gnomad ASJ exome

AF:

0.0420

Gnomad EAS exome

AF:

0.0526

Gnomad FIN exome

AF:

0.176

Gnomad NFE exome

AF:

0.102

Gnomad OTH exome

AF:

0.0900

GnomAD4 exome

AF:

0.101

AC:

144890

AN:

1439756

Hom.:

8142

Cov.:

AF XY:

0.104

AC XY:

74149

AN XY:

715940

show subpopulations

African (AFR)

AF:

0.0138

AC:

455

AN:

32984

American (AMR)

AF:

0.0693

AC:

3014

AN:

43520

Ashkenazi Jewish (ASJ)

AF:

0.0450

AC:

1157

AN:

25704

East Asian (EAS)

AF:

0.0763

AC:

2961

AN:

38800

South Asian (SAS)

AF:

0.186

AC:

15813

AN:

84968

European-Finnish (FIN)

AF:

0.173

AC:

7959

AN:

45920

Middle Eastern (MID)

AF:

0.0946

AC:

393

AN:

4156

European-Non Finnish (NFE)

AF:

0.0976

AC:

107770

AN:

1104280

Other (OTH)

AF:

0.0903

AC:

5368

AN:

59424

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

6551

13103

19654

26206

32757

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3934

7868

11802

15736

19670

<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:

0.0799

AC:

12136

AN:

151920

Hom.:

714

Cov.:

AF XY:

0.0858

AC XY:

6369

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0166

AC:

690

AN:

41482

American (AMR)

AF:

0.0829

AC:

1268

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0513

AC:

178

AN:

3470

East Asian (EAS)

AF:

0.0546

AC:

278

AN:

5088

South Asian (SAS)

AF:

0.183

AC:

878

AN:

4808

European-Finnish (FIN)

AF:

0.189

AC:

1996

AN:

10576

Middle Eastern (MID)

AF:

0.103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0978

AC:

6638

AN:

67890

Other (OTH)

AF:

0.0697

AC:

147

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

559

1118

1678

2237

2796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

146

292

438

584

730

<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:

0.0539

Hom.:

Bravo

AF:

0.0669

Asia WGS

AF:

0.105

AC:

365

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cleidocranial dysostosis;C3549874:Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

8.0

(source)

DANN

Benign

0.89

PhyloP100

-1.4

PromoterAI

-0.058

Neutral

(source)

Mutation Taster

=100/0

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over