rs6930053

Positions:

• chr6-45521021-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1021+8614T>C		intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.979+8614T>C		intron_variant			NP_001356334.1
RUNX2	NM_001015051.4	c.1021+8614T>C		intron_variant			NP_001015051.3
RUNX2	NM_001278478.2	c.979+8614T>C		intron_variant			NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.1021+8614T>C		intron_variant			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

Gnomad4 AFR AF: 0.824

Gnomad4 AMR AF: 0.612

Gnomad4 ASJ AF: 0.626

Gnomad4 EAS AF: 0.575

Gnomad4 SAS AF: 0.507

Gnomad4 FIN AF: 0.578

Gnomad4 NFE AF: 0.599

Gnomad4 OTH AF: 0.610

Alfa AF: 0.642 Hom.: 9237

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs6930053; hg19: chr6-45488758;