chr6-45542087-A-G

Variant names:

• chr6-45542087-A-G
• rs1928533
• NM_001024630.4:c.1022-3130A>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.1022-3130A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,878 control chromosomes in the GnomAD database, including 17,828 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 0.46 (17828 hom., cov: 30)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.283
• Publications: 7 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1022-3130A>G		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.980-3130A>G		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1022-4740A>G		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.980-4740A>G		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.1022-3130A>G		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69699 AN: 151760 Hom.: 17783 Cov.: 30

Gnomad AFR AF: 0.678

Gnomad AMI AF: 0.274

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.0402

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.436

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

GnomAD4 genome AF: 0.459 AC: 69785 AN: 151878 Hom.: 17828 Cov.: 30 AF XY: 0.449 AC XY: 33317 AN XY: 74230

African (AFR) AF: 0.679 AC: 28119 AN: 41424

American (AMR) AF: 0.406 AC: 6196 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1489 AN: 3470

East Asian (EAS) AF: 0.0395 AC: 203 AN: 5142

South Asian (SAS) AF: 0.262 AC: 1259 AN: 4810

European-Finnish (FIN) AF: 0.330 AC: 3485 AN: 10550

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.409 AC: 27769 AN: 67910

Other (OTH) AF: 0.431 AC: 907 AN: 2106

Alfa AF: 0.422 Hom.: 24414

Bravo AF: 0.475

Asia WGS AF: 0.183 AC: 641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.58
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1928533; hg19: chr6-45509824;