ENST00000576263.5:c.1021+46988G>A

Variant names:

• chr6-45559395-G-A
• rs1200425
• ENST00000576263.5:c.1021+46988G>A

Variant summary

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

The ENST00000576263.5(RUNX2):​c.1021+46988G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.446 in 152,014 control chromosomes in the GnomAD database, including 15,987 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 0.45 (15987 hom., cov: 32)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.781
• Publications: 18 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000576263.5	c.1021+46988G>A		intron_variant	Intron 6 of 6	5		ENSP00000458178.1
RUNX2	ENST00000478660.6	n.*178+45742G>A		intron_variant	Intron 5 of 5	5		ENSP00000460188.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67689 AN: 151896 Hom.: 15957 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.446 AC: 67766 AN: 152014 Hom.: 15987 Cov.: 32 AF XY: 0.444 AC XY: 33019 AN XY: 74298

African (AFR) AF: 0.603 AC: 25003 AN: 41434

American (AMR) AF: 0.455 AC: 6957 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 1339 AN: 3464

East Asian (EAS) AF: 0.306 AC: 1587 AN: 5178

South Asian (SAS) AF: 0.301 AC: 1451 AN: 4822

European-Finnish (FIN) AF: 0.407 AC: 4300 AN: 10556

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.382 AC: 25936 AN: 67960

Other (OTH) AF: 0.399 AC: 842 AN: 2110

Alfa AF: 0.398 Hom.: 23497

Bravo AF: 0.459

Asia WGS AF: 0.308 AC: 1074 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.0
DANN	Benign	0.52
PhyloP100		0.78
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: rs1200425; hg19: chr6-45527132;