6-45422788-C-G

Variant names:

• chr6-45422788-C-G
• rs372138746
• NM_001024630.4:c.254C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001024630.4(RUNX2):​c.254C>G​(p.Ala85Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,342,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A85V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.79
• 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17329234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.254C>G	p.Ala85Gly	missense_variant	Exon 3 of 9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.212C>G	p.Ala71Gly	missense_variant	Exon 1 of 7		NP_001356334.1
RUNX2	NM_001015051.4	c.254C>G	p.Ala85Gly	missense_variant	Exon 3 of 8		NP_001015051.3
RUNX2	NM_001278478.2	c.212C>G	p.Ala71Gly	missense_variant	Exon 1 of 6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.254C>G	p.Ala85Gly	missense_variant	Exon 3 of 9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.45e-7 AC: 1 AN: 1342800 Hom.: 0 Cov.: 35 AF XY: 0.00000150 AC XY: 1 AN XY: 664562

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

African (AFR) AF: 0.00 AC: 0 AN: 27122

American (AMR) AF: 0.00 AC: 0 AN: 25186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22536

East Asian (EAS) AF: 0.00 AC: 0 AN: 30372

South Asian (SAS) AF: 0.00 AC: 0 AN: 69660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4954

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061582

Other (OTH) AF: 0.00 AC: 0 AN: 55074

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;D;D;D;.;T;.;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.90	D;.;.;D;.;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;N;N;N;N;.;.;.
PhyloP100		1.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.0	.;N;.;N;N;.;N;.
REVEL	Benign	0.064
Sift	Pathogenic	0.0	.;T;.;T;T;.;T;.
Sift4G	Benign	0.43	T;T;.;T;T;T;T;T
Vest4		0.37
ClinPred		0.61	D
GERP RS		3.5
PromoterAI		-0.051	Neutral
Varity_R		0.083
gMVP		0.52
Mutation Taster		=88/12	polymorphism

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: rs372138746; hg19: chr6-45390525;