rs717987

Variant names:

• chr6-45389246-A-G
• rs717987
• NM_001024630.4:c.59-33347A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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=-0.55).
• 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 rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-33347A>G		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.59-33347A>G		intron_variant	Intron 2 of 7		NP_001015051.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-33347A>G		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1

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

African (AFR) AF: 0.0649 AC: 2698 AN: 41580

American (AMR) AF: 0.230 AC: 3514 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 585 AN: 3470

East Asian (EAS) AF: 0.301 AC: 1558 AN: 5178

South Asian (SAS) AF: 0.132 AC: 635 AN: 4826

European-Finnish (FIN) AF: 0.132 AC: 1398 AN: 10602

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8474 AN: 68014

Other (OTH) AF: 0.135 AC: 285 AN: 2112

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
PhyloP100		0.69
Mutation Taster		=99/1	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: rs717987; hg19: chr6-45356983;