rs1554384228

Variant names:

• chr6-45422749-AG-A
• rs1554384228
• NM_001024630.4:c.217delG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PVS1 PP5 BS2

The NM_001024630.4(RUNX2):​c.217delG​(p.Ala73ArgfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000457 in 1,531,060 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A73A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000043 (1 hom.)
• Consequence: RUNX2 NM_001024630.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 0.995
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-45422749-AG-A is Pathogenic according to our data. Variant chr6-45422749-AG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 548612.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.217delG	p.Ala73ArgfsTer71	frameshift	Exon 3 of 9	NP_001019801.3	Q13950-1
	RUNX2	NM_001369405.1		c.175delG	p.Ala59ArgfsTer71	frameshift	Exon 1 of 7	NP_001356334.1	Q13950-2
	RUNX2	NM_001015051.4		c.217delG	p.Ala73ArgfsTer71	frameshift	Exon 3 of 8	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.217delG	p.Ala73ArgfsTer71	frameshift	Exon 3 of 9	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000359524.7	TSL:1	c.175delG	p.Ala59ArgfsTer71	frameshift	Exon 1 of 7	ENSP00000352514.5	Q13950-2
	RUNX2	ENST00000625924.1	TSL:1	c.175delG	p.Ala59ArgfsTer71	frameshift	Exon 1 of 6	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151186 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000435 AC: 6 AN: 1379874 Hom.: 1 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 685050

African (AFR) AF: 0.00 AC: 0 AN: 28594

American (AMR) AF: 0.00 AC: 0 AN: 32990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23584

East Asian (EAS) AF: 0.00 AC: 0 AN: 32500

South Asian (SAS) AF: 0.00 AC: 0 AN: 75430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5326

European-Non Finnish (NFE) AF: 0.00000372 AC: 4 AN: 1075532

Other (OTH) AF: 0.0000354 AC: 2 AN: 56490

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151186 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73800

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41212

American (AMR) AF: 0.00 AC: 0 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67738

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cleidocranial dysostosis (1)
1	-	-	Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.99
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1554384228; hg19: chr6-45390486;