rs485817

Variant names:

• chr6-45555675-A-G
• rs485817
• ENST00000576263.5:c.1021+43268A>G

Variant summary

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

The ENST00000576263.5(RUNX2):​c.1021+43268A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.488 in 151,556 control chromosomes in the GnomAD database, including 18,122 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 0.49 (18122 hom., cov: 30)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 4 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000576263.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000576263.5	TSL:5	c.1021+43268A>G		intron	N/A	ENSP00000458178.1	I3L0L0
	RUNX2	ENST00000478660.6	TSL:5	n.*178+42022A>G		intron	N/A	ENSP00000460188.1	I3L354

Frequencies

GnomAD3 genomes AF: 0.488 AC: 73873 AN: 151438 Hom.: 18124 Cov.: 30

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.493

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.522

Gnomad OTH AF: 0.484

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

GnomAD4 genome AF: 0.488 AC: 73890 AN: 151556 Hom.: 18122 Cov.: 30 AF XY: 0.481 AC XY: 35619 AN XY: 74072

African (AFR) AF: 0.491 AC: 20248 AN: 41254

American (AMR) AF: 0.451 AC: 6874 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1674 AN: 3456

East Asian (EAS) AF: 0.255 AC: 1307 AN: 5134

South Asian (SAS) AF: 0.357 AC: 1715 AN: 4800

European-Finnish (FIN) AF: 0.493 AC: 5182 AN: 10516

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.522 AC: 35405 AN: 67844

Other (OTH) AF: 0.479 AC: 1010 AN: 2108

Alfa AF: 0.507 Hom.: 37940

Bravo AF: 0.487

Asia WGS AF: 0.302 AC: 1051 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.49
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs485817; hg19: chr6-45523412;