6-45422767-C-CAGGA

Variant names:

• chr6-45422767-C-CAGGA
• rs1338909353
• NM_001024630.4:c.233_234insAGGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 10P and 4B. PVS1 PM2 BS2

The NM_001024630.4(RUNX2):​c.233_234insAGGA​(p.Ala79GlyfsTer83) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000452 in 1,106,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A78A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000045 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.250
• 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: 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.233_234insAGGA	p.Ala79GlyfsTer83	frameshift	Exon 3 of 9	NP_001019801.3
	RUNX2	NM_001369405.1		c.191_192insAGGA	p.Ala65GlyfsTer83	frameshift	Exon 1 of 7	NP_001356334.1
	RUNX2	NM_001015051.4		c.233_234insAGGA	p.Ala79GlyfsTer83	frameshift	Exon 3 of 8	NP_001015051.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.233_234insAGGA	p.Ala79GlyfsTer83	frameshift	Exon 3 of 9	ENSP00000495497.1
	RUNX2	ENST00000359524.7	TSL:1	c.191_192insAGGA	p.Ala65GlyfsTer83	frameshift	Exon 1 of 7	ENSP00000352514.5
	RUNX2	ENST00000625924.1	TSL:1	c.191_192insAGGA	p.Ala65GlyfsTer83	frameshift	Exon 1 of 6	ENSP00000485863.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD2 exomes AF: 0.0000202 AC: 2 AN: 98962 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000437

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000452 AC: 5 AN: 1106248 Hom.: 0 Cov.: 34 AF XY: 0.00000184 AC XY: 1 AN XY: 544400

African (AFR) AF: 0.00 AC: 0 AN: 24524

American (AMR) AF: 0.00 AC: 0 AN: 15606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17362

East Asian (EAS) AF: 0.00 AC: 0 AN: 27036

South Asian (SAS) AF: 0.00 AC: 0 AN: 54560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4196

European-Non Finnish (NFE) AF: 0.00000454 AC: 4 AN: 880860

Other (OTH) AF: 0.0000221 AC: 1 AN: 45148

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cleidocranial dysostosis (1)
-	1	-	Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.25
Mutation Taster		=179/21	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1338909353; hg19: chr6-45390504;