rs104893990

Variant names:

• chr6-45432011-G-A
• rs104893990
• NM_001024630.4:c.572G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_001024630.4(RUNX2):​c.572G>A​(p.Ser191Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.56

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain Runt (size 128) in uniprot entity RUNX2_HUMAN there are 37 pathogenic changes around while only 0 benign (100%) in NM_001024630.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881
• PP5: Variant 6-45432011-G-A is Pathogenic according to our data. Variant chr6-45432011-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9299.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.572G>A	p.Ser191Asn	missense_variant	Exon 4 of 9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.530G>A	p.Ser177Asn	missense_variant	Exon 2 of 7		NP_001356334.1
RUNX2	NM_001015051.4	c.572G>A	p.Ser191Asn	missense_variant	Exon 4 of 8		NP_001015051.3
RUNX2	NM_001278478.2	c.530G>A	p.Ser177Asn	missense_variant	Exon 2 of 6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.572G>A	p.Ser191Asn	missense_variant	Exon 4 of 9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cleidocranial dysostosis Pathogenic:1

Jul 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Sep 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 191 of the RUNX2 protein (p.Ser191Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cleidocranial dysplasia (PMID: 9207800; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 9299). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RUNX2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RUNX2 function (PMID: 9207800). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	.;D;D;D;.;D;.;D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;M;M;M;M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	.;D;.;D;D;.;D;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;D;.;D;D;.;D;.
Sift4G	Pathogenic	0.0010	D;D;.;D;D;D;D;D
Polyphen		0.95, 1.0	.;P;P;P;.;.;D;.
Vest4		0.94
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.97

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

Other links and lift over

dbSNP: rs104893990; hg19: chr6-45399748;