rs13207392

Variant names:

• chr6-45528719-C-T
• rs13207392
• NM_001024630.4:c.1021+16312C>T

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+16312C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 151,976 control chromosomes in the GnomAD database, including 11,630 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 0.36 (11630 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.293
• 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1021+16312C>T		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.979+16312C>T		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1021+16312C>T		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.979+16312C>T		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+16312C>T		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55051 AN: 151860 Hom.: 11615 Cov.: 32

Gnomad AFR AF: 0.595

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.0434

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.363 AC: 55103 AN: 151976 Hom.: 11630 Cov.: 32 AF XY: 0.358 AC XY: 26606 AN XY: 74292

African (AFR) AF: 0.594 AC: 24645 AN: 41458

American (AMR) AF: 0.301 AC: 4601 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3470

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5174

South Asian (SAS) AF: 0.253 AC: 1215 AN: 4804

European-Finnish (FIN) AF: 0.282 AC: 2967 AN: 10532

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19477 AN: 67944

Other (OTH) AF: 0.310 AC: 654 AN: 2108

Alfa AF: 0.351 Hom.: 1362

Bravo AF: 0.372

Asia WGS AF: 0.165 AC: 578 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	1.6
DANN	Benign	0.60
PhyloP100		-0.29
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: rs13207392; hg19: chr6-45496456;