chr6-45547270-G-C

Variant names:

• chr6-45547270-G-C
• rs11498198
• NM_001024630.4:c.1531G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001024630.4(RUNX2):​c.1531G>C​(p.Gly511Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G511S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 11 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.1531G>C	p.Gly511Arg	missense	Exon 9 of 9	NP_001019801.3	Q13950-1
	RUNX2	NM_001369405.1		c.1489G>C	p.Gly497Arg	missense	Exon 7 of 7	NP_001356334.1	Q13950-2
	RUNX2	NM_001015051.4		c.1465G>C	p.Gly489Arg	missense	Exon 8 of 8	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.1531G>C	p.Gly511Arg	missense	Exon 9 of 9	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000359524.7	TSL:1	c.1489G>C	p.Gly497Arg	missense	Exon 7 of 7	ENSP00000352514.5	Q13950-2
	RUNX2	ENST00000625924.1	TSL:1	c.1423G>C	p.Gly475Arg	missense	Exon 6 of 6	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.60
MVP		0.57
MPC		1.7
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.76
gMVP		0.59
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs11498198; hg19: chr6-45515007;