rs397515538

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001024630.4(RUNX2):c.90delC(p.Ser31fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,605,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RUNX2
NM_001024630.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.871

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 44 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-45422617-GC-G is Pathogenic according to our data. Variant chr6-45422617-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 929063.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4 linkuse as main transcript	c.90delC	p.Ser31fs	frameshift_variant	3/9	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 linkuse as main transcript	c.48delC	p.Ser17fs	frameshift_variant	1/7		NP_001356334.1
RUNX2	NM_001015051.4 linkuse as main transcript	c.90delC	p.Ser31fs	frameshift_variant	3/8		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 linkuse as main transcript	c.48delC	p.Ser17fs	frameshift_variant	1/6		NP_001265407.1	Q32MY8A0A0D9SEN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 linkuse as main transcript	c.90delC	p.Ser31fs	frameshift_variant	3/9		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1454168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151218

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73760

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cleidocranial dysostosis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 11, 2019

Variant summary: RUNX2 c.90delC (p.Ser31ProfsX9) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay (NMD), which are commonly known mechanisms for disease. However, downstream from the variant, there is a second ATG codon in an appropriate context for translational initiation, and at least one in vitro study has described that a construct containing only the second ATG codon (i.e. Met39) was nearly as active as the WT construct containing both; on the other hand, the same study demonstrated that deletion of the first 38 amino acid residues led to a partial decrease in transactivation activity (PMID: 9632804). The variant was observed in 1/31166 control chromosomes (gnomAD database, genome dataset). To our knowledge, no occurrence of c.90delC in individuals affected with Cleidocranial Dysplasia (CCD) and no experimental evidence demonstrating its impact on protein function have been reported. However, different variant, affecting the same nucleotide position, and resulting in a similar protein level change (i.e. a frameshift), RUNX2 c.90dupC (p.Ser31Leufs), has been described in the literature in a proband with mild CCD, and with significant intrafamilial variability in expressivity, leading the authors to interpret this variant as a hypomorphic allele, which could be possibly explained by the utilization of the downstream ATG codon for translational initiation (PMID: 10545612). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant of interest could possibly represent a hypomorphic variant associated with milder phenotype, or potentially even a typical truncating variant associated with a more severe phenotype (based on NMD), therefore it was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over