rs2396442

Variant names:

• chr6-45489244-T-C
• rs2396442
• NM_001024630.4:c.686-2697T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):​c.686-2697T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,098 control chromosomes in the GnomAD database, including 6,284 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 0.27 (6284 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.357
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, Orphanet
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.686-2697T>C		intron	N/A	NP_001019801.3	Q13950-1
	RUNX2	NM_001369405.1		c.644-2697T>C		intron	N/A	NP_001356334.1	Q13950-2
	RUNX2	NM_001015051.4		c.686-2697T>C		intron	N/A	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.686-2697T>C		intron	N/A	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000359524.7	TSL:1	c.644-2697T>C		intron	N/A	ENSP00000352514.5	Q13950-2
	RUNX2	ENST00000625924.1	TSL:1	c.644-2697T>C		intron	N/A	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41702 AN: 151980 Hom.: 6283 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.274 AC: 41697 AN: 152098 Hom.: 6284 Cov.: 32 AF XY: 0.272 AC XY: 20243 AN XY: 74316

African (AFR) AF: 0.168 AC: 6974 AN: 41506

American (AMR) AF: 0.289 AC: 4422 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3470

East Asian (EAS) AF: 0.0562 AC: 291 AN: 5182

South Asian (SAS) AF: 0.263 AC: 1268 AN: 4820

European-Finnish (FIN) AF: 0.311 AC: 3281 AN: 10552

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23269 AN: 67964

Other (OTH) AF: 0.269 AC: 568 AN: 2110

Alfa AF: 0.305 Hom.: 1505

Bravo AF: 0.267

Asia WGS AF: 0.159 AC: 555 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.58
PhyloP100		0.36
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: rs2396442; hg19: chr6-45456981;