6-45518470-C-G

Variant names:

• chr6-45518470-C-G
• rs7771889
• NM_001024630.4:c.1021+6063C>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.1021+6063C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 151,844 control chromosomes in the GnomAD database, including 12,306 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 0.38 (12306 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616
• Publications: 5 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 = 0.595 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.1021+6063C>G		intron	N/A	NP_001019801.3
	RUNX2	NM_001369405.1		c.979+6063C>G		intron	N/A	NP_001356334.1
	RUNX2	NM_001015051.4		c.1021+6063C>G		intron	N/A	NP_001015051.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.1021+6063C>G		intron	N/A	ENSP00000495497.1
	RUNX2	ENST00000359524.7	TSL:1	c.979+6063C>G		intron	N/A	ENSP00000352514.5
	RUNX2	ENST00000625924.1	TSL:1	c.979+6063C>G		intron	N/A	ENSP00000485863.1

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57527 AN: 151726 Hom.: 12292 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.379 AC: 57574 AN: 151844 Hom.: 12306 Cov.: 32 AF XY: 0.378 AC XY: 28011 AN XY: 74184

African (AFR) AF: 0.602 AC: 24895 AN: 41380

American (AMR) AF: 0.354 AC: 5399 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 1036 AN: 3468

East Asian (EAS) AF: 0.265 AC: 1370 AN: 5162

South Asian (SAS) AF: 0.296 AC: 1426 AN: 4810

European-Finnish (FIN) AF: 0.282 AC: 2965 AN: 10506

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.287 AC: 19526 AN: 67934

Other (OTH) AF: 0.325 AC: 687 AN: 2112

Alfa AF: 0.207 Hom.: 428

Bravo AF: 0.394

Asia WGS AF: 0.266 AC: 929 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.75
PhyloP100		-0.62
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: rs7771889; hg19: chr6-45486207;