rs1200426

Variant names:

• chr6-45559205-G-T
• rs1200426
• ENST00000576263.5:c.1021+46798G>T

Variant summary

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

The ENST00000576263.5(RUNX2):​c.1021+46798G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 152,098 control chromosomes in the GnomAD database, including 3,052 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 0.19 (3052 hom., cov: 32)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 6 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.244 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+46798G>T		intron_variant	Intron 6 of 6	5		ENSP00000458178.1
RUNX2	ENST00000478660.6	n.*178+45552G>T		intron_variant	Intron 5 of 5	5		ENSP00000460188.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28388 AN: 151980 Hom.: 3057 Cov.: 32

Gnomad AFR AF: 0.0928

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.190

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

GnomAD4 genome AF: 0.187 AC: 28376 AN: 152098 Hom.: 3052 Cov.: 32 AF XY: 0.185 AC XY: 13723 AN XY: 74354

African (AFR) AF: 0.0926 AC: 3844 AN: 41498

American (AMR) AF: 0.219 AC: 3352 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 754 AN: 3472

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5180

South Asian (SAS) AF: 0.177 AC: 851 AN: 4806

European-Finnish (FIN) AF: 0.203 AC: 2148 AN: 10566

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16772 AN: 67982

Other (OTH) AF: 0.188 AC: 396 AN: 2108

Alfa AF: 0.225 Hom.: 12277

Bravo AF: 0.184

Asia WGS AF: 0.0970 AC: 338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.40
PhyloP100		1.2
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: rs1200426; hg19: chr6-45526942;