Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001024630.4(RUNX2):c.240G>A(p.Ala80Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,487,112 control chromosomes in the GnomAD database, including 8,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 711 hom., cov: 31)

Exomes 𝑓: 0.10 ( 8082 hom. )

Consequence

RUNX2
NM_001024630.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.758

Publications

12 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

RUNX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 6-45422774-G-A is Benign according to our data. Variant chr6-45422774-G-A is described in ClinVar as Benign. ClinVar VariationId is 196301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.758 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 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	HGVSp	Effect	Exon Rank	Protein
RUNX2	NM_001024630.4	MANE Select	c.240G>A	p.Ala80Ala	synonymous	Exon 3 of 9	NP_001019801.3
RUNX2	NM_001369405.1		c.198G>A	p.Ala66Ala	synonymous	Exon 1 of 7	NP_001356334.1
RUNX2	NM_001015051.4		c.240G>A	p.Ala80Ala	synonymous	Exon 3 of 8	NP_001015051.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RUNX2	ENST00000647337.2	MANE Select	c.240G>A	p.Ala80Ala	synonymous	Exon 3 of 9	ENSP00000495497.1
RUNX2	ENST00000359524.7	TSL:1	c.198G>A	p.Ala66Ala	synonymous	Exon 1 of 7	ENSP00000352514.5
RUNX2	ENST00000625924.1	TSL:1	c.198G>A	p.Ala66Ala	synonymous	Exon 1 of 6	ENSP00000485863.1

Frequencies

GnomAD3 genomes

AF:

0.0801

AC:

12115

AN:

151292

Hom.:

714

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0825

Gnomad ASJ

AF:

0.0511

Gnomad EAS

AF:

0.0553

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.0987

Gnomad NFE

AF:

0.0980

Gnomad OTH

AF:

0.0705

GnomAD2 exomes

AF:

0.133

AC:

16498

AN:

123672

AF XY:

0.138

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.0970

Gnomad ASJ exome

AF:

0.0469

Gnomad EAS exome

AF:

0.0861

Gnomad FIN exome

AF:

0.188

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.104

AC:

138713

AN:

1335712

Hom.:

8082

Cov.:

AF XY:

0.107

AC XY:

70581

AN XY:

661156

show subpopulations

African (AFR)

AF:

0.0135

AC:

365

AN:

26976

American (AMR)

AF:

0.0868

AC:

2017

AN:

23228

Ashkenazi Jewish (ASJ)

AF:

0.0471

AC:

1046

AN:

22230

East Asian (EAS)

AF:

0.0861

AC:

2632

AN:

30564

South Asian (SAS)

AF:

0.200

AC:

13942

AN:

69872

European-Finnish (FIN)

AF:

0.180

AC:

8437

AN:

46854

Middle Eastern (MID)

AF:

0.0924

AC:

462

AN:

5002

European-Non Finnish (NFE)

AF:

0.0992

AC:

104785

AN:

1056226

Other (OTH)

AF:

0.0918

AC:

5027

AN:

54760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

5944

11888

17831

23775

29719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3892

7784

11676

15568

19460

<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:

0.0800

AC:

12109

AN:

151400

Hom.:

711

Cov.:

AF XY:

0.0860

AC XY:

6365

AN XY:

74002

show subpopulations

African (AFR)

AF:

0.0165

AC:

682

AN:

41278

American (AMR)

AF:

0.0824

AC:

1255

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.0511

AC:

177

AN:

3462

East Asian (EAS)

AF:

0.0555

AC:

283

AN:

5098

South Asian (SAS)

AF:

0.181

AC:

873

AN:

4812

European-Finnish (FIN)

AF:

0.190

AC:

1985

AN:

10432

Middle Eastern (MID)

AF:

0.103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0980

AC:

6644

AN:

67796

Other (OTH)

AF:

0.0703

AC:

147

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

522

1044

1566

2088

2610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0562

Hom.:

Bravo

AF:

0.0668

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Cleidocranial dysostosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

0.76

PromoterAI

0.018

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.

rs6921145

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over