rs717987

chr6-45389246-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):c.59-33347A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,264 control chromosomes in the GnomAD database, including 1,537 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 0.13 (1537 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.687

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=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX2	NM_001024630.4	c.59-33347A>G		intron_variant		ENST00000647337.2
RUNX2	NM_001015051.4	c.59-33347A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-33347A>G		intron_variant			NM_001024630.4	P4

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19243 AN: 152146 Hom.: 1531 Cov.: 32

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.169

Gnomad EAS AF: 0.300

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.137

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

GnomAD4 genome AF: 0.126 AC: 19259 AN: 152264 Hom.: 1537 Cov.: 32 AF XY: 0.130 AC XY: 9695 AN XY: 74440

Gnomad4 AFR AF: 0.0649

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.169

Gnomad4 EAS AF: 0.301

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.135

Alfa AF: 0.128 Hom.: 185

Bravo AF: 0.134

Asia WGS AF: 0.196 AC: 679 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	12
Dann	Benign	0.87

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: rs717987; hg19: chr6-45356983;