rs9472494

Variant names:

• chr6-45484099-C-T
• rs9472494
• NM_001024630.4:c.686-7842C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):​c.686-7842C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 151,968 control chromosomes in the GnomAD database, including 7,462 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7462 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.29
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.686-7842C>T		intron	N/A	NP_001019801.3	Q13950-1
	RUNX2	NM_001369405.1		c.644-7842C>T		intron	N/A	NP_001356334.1	Q13950-2
	RUNX2	NM_001015051.4		c.686-7842C>T		intron	N/A	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.686-7842C>T		intron	N/A	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000359524.7	TSL:1	c.644-7842C>T		intron	N/A	ENSP00000352514.5	Q13950-2
	RUNX2	ENST00000625924.1	TSL:1	c.644-7842C>T		intron	N/A	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46744 AN: 151850 Hom.: 7459 Cov.: 32

Gnomad AFR AF: 0.280

Gnomad AMI AF: 0.209

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.399

Gnomad EAS AF: 0.0502

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.299

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.308 AC: 46762 AN: 151968 Hom.: 7462 Cov.: 32 AF XY: 0.305 AC XY: 22655 AN XY: 74254

African (AFR) AF: 0.280 AC: 11610 AN: 41438

American (AMR) AF: 0.301 AC: 4600 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 1383 AN: 3470

East Asian (EAS) AF: 0.0495 AC: 256 AN: 5170

South Asian (SAS) AF: 0.283 AC: 1358 AN: 4804

European-Finnish (FIN) AF: 0.312 AC: 3286 AN: 10536

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23377 AN: 67970

Other (OTH) AF: 0.296 AC: 626 AN: 2114

Alfa AF: 0.334 Hom.: 9940

Bravo AF: 0.305

Asia WGS AF: 0.168 AC: 586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.72
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs9472494; hg19: chr6-45451836;