6-45547270-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001024630.4(RUNX2):c.1531G>A(p.Gly511Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,152 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0083 ( 8 hom., cov: 32)

Exomes 𝑓: 0.011 ( 87 hom. )

Consequence

RUNX2
NM_001024630.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 9.60

Publications

11 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.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.6033 (below the threshold of 3.09). Trascript score misZ: 1.7818 (below the threshold of 3.09). GenCC associations: The gene is linked to cleidocranial dysplasia 1, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.008539617).

BP6

Variant 6-45547270-G-A is Benign according to our data. Variant chr6-45547270-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 357096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0083 (1264/152302) while in subpopulation NFE AF = 0.0114 (777/68030). AF 95% confidence interval is 0.0108. There are 8 homozygotes in GnomAd4. There are 620 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1264 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4 link	c.1531G>A	p.Gly511Ser	missense_variant	Exon 9 of 9	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 link	c.1489G>A	p.Gly497Ser	missense_variant	Exon 7 of 7		NP_001356334.1
RUNX2	NM_001015051.4 link	c.1465G>A	p.Gly489Ser	missense_variant	Exon 8 of 8		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 link	c.1423G>A	p.Gly475Ser	missense_variant	Exon 6 of 6		NP_001265407.1	Q32MY8A0A0D9SEN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 link	c.1531G>A	p.Gly511Ser	missense_variant	Exon 9 of 9		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.00831

AC:

1264

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00442

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00714

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00764

AC:

1919

AN:

251052

AF XY:

0.00792

show subpopulations

Gnomad AFR exome

AF:

0.00425

Gnomad AMR exome

AF:

0.00454

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0121

Gnomad NFE exome

AF:

0.0114

Gnomad OTH exome

AF:

0.00996

GnomAD4 exome

AF:

0.0106

AC:

15454

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

7514

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00373

AC:

125

AN:

33480

American (AMR)

AF:

0.00463

AC:

207

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00196

AC:

169

AN:

86256

European-Finnish (FIN)

AF:

0.0121

AC:

649

AN:

53420

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0123

AC:

13649

AN:

1111974

Other (OTH)

AF:

0.00972

AC:

587

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

851

1702

2554

3405

4256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

510

1020

1530

2040

2550

<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:

0.00830

AC:

1264

AN:

152302

Hom.:

Cov.:

AF XY:

0.00832

AC XY:

620

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00440

AC:

183

AN:

41556

American (AMR)

AF:

0.00713

AC:

109

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00186

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

777

AN:

68030

Other (OTH)

AF:

0.00851

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

140

210

280

350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00936

Hom.:

Bravo

AF:

0.00804

TwinsUK

AF:

0.0116

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.0114

AC:

ExAC

AF:

0.00812

AC:

986

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RUNX2: BS1, BS2 -

Oct 18, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 17, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 30, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 32360898) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Cleidocranial dysostosis

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign, for Cleidocranial dysplasia, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:10521292). -

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

Benign:1

Aug 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

.;D;D;D;.;.;T

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;.;D;.;D;D

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M;M;M;.;.;.

PhyloP100

9.6

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-2.8

.;D;.;D;D;D;.

REVEL

Uncertain

0.33

Sift

Benign

0.070

.;T;.;T;T;T;.

Sift4G

Benign

0.096

T;T;.;T;T;T;T

Polyphen

1.0

.;D;D;D;.;D;.

Vest4

0.46

MVP

0.56

MPC

1.6

ClinPred

0.016

GERP RS

5.8

Varity_R

0.49

gMVP

0.48

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over