chr6-45557209-A-G

Variant names:

• chr6-45557209-A-G
• rs545289
• ENST00000576263.5:c.1021+44802A>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+44802A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 152,042 control chromosomes in the GnomAD database, including 21,580 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 0.51 (21580 hom., cov: 32)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 2 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 (AFR) allele frequency at 95% confidence interval = 0.754 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+44802A>G		intron	N/A	ENSP00000458178.1	I3L0L0
	RUNX2	ENST00000478660.6	TSL:5	n.*178+43556A>G		intron	N/A	ENSP00000460188.1	I3L354

Frequencies

GnomAD3 genomes AF: 0.507 AC: 77073 AN: 151924 Hom.: 21539 Cov.: 32

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.510

Gnomad ASJ AF: 0.400

Gnomad EAS AF: 0.310

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.459

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

GnomAD4 genome AF: 0.508 AC: 77169 AN: 152042 Hom.: 21580 Cov.: 32 AF XY: 0.504 AC XY: 37445 AN XY: 74326

African (AFR) AF: 0.761 AC: 31543 AN: 41462

American (AMR) AF: 0.510 AC: 7797 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.400 AC: 1388 AN: 3468

East Asian (EAS) AF: 0.310 AC: 1602 AN: 5166

South Asian (SAS) AF: 0.334 AC: 1610 AN: 4824

European-Finnish (FIN) AF: 0.404 AC: 4271 AN: 10566

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27610 AN: 67960

Other (OTH) AF: 0.456 AC: 961 AN: 2108

Alfa AF: 0.431 Hom.: 12163

Bravo AF: 0.530

Asia WGS AF: 0.324 AC: 1126 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	2.9
DANN	Benign	0.55
PhyloP100		-0.14
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: rs545289; hg19: chr6-45524946;