ENST00000576263.5:c.1021+43784C>T

Variant names:

• chr6-45556191-C-T
• rs675613
• ENST00000576263.5:c.1021+43784C>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+43784C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 152,248 control chromosomes in the GnomAD database, including 71,685 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 0.97 (71685 hom., cov: 31)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 1 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.985 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+43784C>T		intron_variant	Intron 6 of 6	5		ENSP00000458178.1
RUNX2	ENST00000478660.6	n.*178+42538C>T		intron_variant	Intron 5 of 5	5		ENSP00000460188.1

Frequencies

GnomAD3 genomes AF: 0.970 AC: 147524 AN: 152130 Hom.: 71621 Cov.: 31

Gnomad AFR AF: 0.993

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.961

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 0.868

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.941

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.975

Gnomad OTH AF: 0.975

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

GnomAD4 genome AF: 0.970 AC: 147648 AN: 152248 Hom.: 71685 Cov.: 31 AF XY: 0.966 AC XY: 71850 AN XY: 74416

African (AFR) AF: 0.993 AC: 41291 AN: 41562

American (AMR) AF: 0.961 AC: 14699 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 3412 AN: 3472

East Asian (EAS) AF: 0.869 AC: 4488 AN: 5166

South Asian (SAS) AF: 0.871 AC: 4204 AN: 4824

European-Finnish (FIN) AF: 0.941 AC: 9964 AN: 10586

Middle Eastern (MID) AF: 0.973 AC: 286 AN: 294

European-Non Finnish (NFE) AF: 0.975 AC: 66339 AN: 68026

Other (OTH) AF: 0.975 AC: 2055 AN: 2108

Alfa AF: 0.976 Hom.: 8582

Bravo AF: 0.973

Asia WGS AF: 0.889 AC: 3094 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.82
DANN	Benign	0.59
PhyloP100		-0.075
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: rs675613; hg19: chr6-45523928;