rs6930053

Variant names:

• chr6-45521021-T-C
• rs6930053
• NM_001024630.4:c.1021+8614T>C

Variant summary

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

The NM_001024630.4(RUNX2):​c.1021+8614T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 152,114 control chromosomes in the GnomAD database, including 33,648 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 0.66 (33648 hom., cov: 33)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.34
• Publications: 9 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1021+8614T>C		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.979+8614T>C		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1021+8614T>C		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.979+8614T>C		intron_variant	Intron 5 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.1021+8614T>C		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99692 AN: 151996 Hom.: 33598 Cov.: 33

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.575

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.618

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

GnomAD4 genome AF: 0.656 AC: 99783 AN: 152114 Hom.: 33648 Cov.: 33 AF XY: 0.652 AC XY: 48429 AN XY: 74334

African (AFR) AF: 0.824 AC: 34197 AN: 41516

American (AMR) AF: 0.612 AC: 9347 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2172 AN: 3470

East Asian (EAS) AF: 0.575 AC: 2968 AN: 5166

South Asian (SAS) AF: 0.507 AC: 2448 AN: 4824

European-Finnish (FIN) AF: 0.578 AC: 6102 AN: 10560

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.599 AC: 40735 AN: 67980

Other (OTH) AF: 0.610 AC: 1288 AN: 2110

Alfa AF: 0.635 Hom.: 14361

Bravo AF: 0.670

Asia WGS AF: 0.518 AC: 1806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.15
DANN	Benign	0.21
PhyloP100		-2.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs6930053; hg19: chr6-45488758;