rs11498198

chr6-45547270-G-Achr6-45547270-G-Cchr6-45547270-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 9.60

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 1264 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX2	NM_001024630.4	c.1531G>A	p.Gly511Ser	missense_variant	9/9	ENST00000647337.2
RUNX2	NM_001369405.1	c.1489G>A	p.Gly497Ser	missense_variant	7/7
RUNX2	NM_001015051.4	c.1465G>A	p.Gly489Ser	missense_variant	8/8
RUNX2	NM_001278478.2	c.1423G>A	p.Gly475Ser	missense_variant	6/6

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1264 AN: 152184 Hom.: 8 Cov.: 32

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.: 9 AF XY: 0.00792 AC XY: 1074 AN XY: 135668

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.: 87 Cov.: 31 AF XY: 0.0103 AC XY: 7514 AN XY: 727228

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.: 8 Cov.: 32 AF XY: 0.00832 AC XY: 620 AN XY: 74478

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.: 11

Bravo AF: 0.00804

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00812 AC: 986

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 18, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RUNX2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2020	This variant is associated with the following publications: (PMID: 32360898) -

Cleidocranial dysostosis Benign:2

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). -
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. -

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	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;D;D
MetaRNN	Benign	0.0085	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
REVEL	Uncertain	0.33
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	T
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

Other links and lift over

dbSNP: rs11498198; hg19: chr6-45515007;