rs11498198

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 [Likely_benign]. Clinvar id is 357096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45547270-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1264 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RUNX2	NM_001024630.4 linkuse as main transcript	c.1531G>A	p.Gly511Ser	missense_variant	9/9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1 linkuse as main transcript	c.1489G>A	p.Gly497Ser	missense_variant	7/7		NP_001356334.1
RUNX2	NM_001015051.4 linkuse as main transcript	c.1465G>A	p.Gly489Ser	missense_variant	8/8		NP_001015051.3
RUNX2	NM_001278478.2 linkuse as main transcript	c.1423G>A	p.Gly475Ser	missense_variant	6/6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 linkuse as main transcript	c.1531G>A	p.Gly511Ser	missense_variant	9/9		NM_001024630.4	ENSP00000495497	P4	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

GnomAD3 exomes

AF:

0.00764

AC:

1919

AN:

251052

Hom.:

AF XY:

0.00792

AC XY:

1074

AN XY:

135668

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 SAS exome

AF:

0.00176

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

Gnomad4 AFR exome

AF:

0.00373

Gnomad4 AMR exome

AF:

0.00463

Gnomad4 ASJ exome

AF:

0.00191

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00196

Gnomad4 FIN exome

AF:

0.0121

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.00972

GnomAD4 genome

AF:

0.00830

AC:

1264

AN:

152302

Hom.:

Cov.:

AF XY:

0.00832

AC XY:

620

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00440

Gnomad4 AMR

AF:

0.00713

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.0150

Gnomad4 NFE

AF:

0.0114

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00921

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RUNX2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	This variant is associated with the following publications: (PMID: 32360898) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Cleidocranial dysostosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 25, 2021

- -

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

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;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over