chr6-45437964-A-G

Variant names:

• chr6-45437964-A-G
• rs104893993
• NM_001024630.4:c.598A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001024630.4(RUNX2):​c.598A>G​(p.Thr200Ala) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 9.32
• Publications: 13 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 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001024630.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 29 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 1.6033 (below the threshold of 3.09). Trascript score misZ: 1.7818 (below the threshold of 3.09). GenCC associations: The gene is linked to cleidocranial dysplasia 1, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 6-45437964-A-G is Pathogenic according to our data. Variant chr6-45437964-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 9304.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.598A>G	p.Thr200Ala	missense_variant	Exon 5 of 9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.556A>G	p.Thr186Ala	missense_variant	Exon 3 of 7		NP_001356334.1
RUNX2	NM_001015051.4	c.598A>G	p.Thr200Ala	missense_variant	Exon 5 of 8		NP_001015051.3
RUNX2	NM_001278478.2	c.556A>G	p.Thr186Ala	missense_variant	Exon 3 of 6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.598A>G	p.Thr200Ala	missense_variant	Exon 5 of 9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cleidocranial dysostosis Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cleidocranial dysplasia 1, forme fruste, dental anomalies only Pathogenic:1

Nov 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 200 of the RUNX2 protein (p.Thr200Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cleidocranial dysplasia (PMID: 10545612; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as CBFA1 T200A. ClinVar contains an entry for this variant (Variation ID: 9304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 does not substantially affect RUNX2 function (PMID: 10545612, 23558979). This variant disrupts the p.Thr200 amino acid residue in RUNX2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19767586). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	.;D;D;D;.;D;.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.9	.;D;.;D;D;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	.;D;.;D;D;.;D;.
Sift4G	Uncertain	0.0020	D;D;.;D;D;D;D;D
Polyphen		1.0, 0.99	.;D;D;D;.;.;D;.
Vest4		0.97
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.96
Mutation Taster		=0/100	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: rs104893993; hg19: chr6-45405701;