6-45558952-C-T

Variant names:

• chr6-45558952-C-T
• rs2153277
• ENST00000576263.5:c.1021+46545C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000576263.5(RUNX2):​c.1021+46545C>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 152,194 control chromosomes in the GnomAD database, including 3,065 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 (3065 hom., cov: 33)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• 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+46545C>T		intron_variant	Intron 6 of 6	5		ENSP00000458178.1
RUNX2	ENST00000478660.6	n.*178+45299C>T		intron_variant	Intron 5 of 5	5		ENSP00000460188.1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28439 AN: 152076 Hom.: 3070 Cov.: 33

Gnomad AFR AF: 0.0931

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: 0.204

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: 28427 AN: 152194 Hom.: 3065 Cov.: 33 AF XY: 0.185 AC XY: 13747 AN XY: 74402

African (AFR) AF: 0.0930 AC: 3864 AN: 41548

American (AMR) AF: 0.220 AC: 3361 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 753 AN: 3468

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5182

South Asian (SAS) AF: 0.177 AC: 853 AN: 4818

European-Finnish (FIN) AF: 0.204 AC: 2154 AN: 10582

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

European-Non Finnish (NFE) AF: 0.247 AC: 16785 AN: 67984

Other (OTH) AF: 0.188 AC: 398 AN: 2112

Alfa AF: 0.229 Hom.: 2196

Bravo AF: 0.184

Asia WGS AF: 0.0960 AC: 336 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	15
DANN	Benign	0.52
PhyloP100		0.24
Mutation Taster		=99/1	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2153277; hg19: chr6-45526689;