rs1321080

Variant names:

• chr6-45390586-G-T
• rs1321080
• NM_001024630.4:c.59-32007G>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.59-32007G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,102 control chromosomes in the GnomAD database, including 3,276 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 0.20 (3276 hom., cov: 33)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-32007G>T		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.59-32007G>T		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.59-32007G>T		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29672 AN: 151984 Hom.: 3278 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.0237

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.183

Gnomad NFE AF: 0.258

Gnomad OTH AF: 0.191

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

GnomAD4 genome AF: 0.195 AC: 29674 AN: 152102 Hom.: 3276 Cov.: 33 AF XY: 0.192 AC XY: 14295 AN XY: 74340

African (AFR) AF: 0.120 AC: 4974 AN: 41504

American (AMR) AF: 0.156 AC: 2377 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 741 AN: 3472

East Asian (EAS) AF: 0.0237 AC: 123 AN: 5184

South Asian (SAS) AF: 0.137 AC: 660 AN: 4826

European-Finnish (FIN) AF: 0.249 AC: 2624 AN: 10544

Middle Eastern (MID) AF: 0.183 AC: 53 AN: 290

European-Non Finnish (NFE) AF: 0.258 AC: 17527 AN: 67974

Other (OTH) AF: 0.189 AC: 400 AN: 2114

Alfa AF: 0.234 Hom.: 18475

Bravo AF: 0.186

Asia WGS AF: 0.0840 AC: 294 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.65
PhyloP100		0.0030
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: rs1321080; hg19: chr6-45358323;