6-45422587-C-T

Position:

• chr6-45422587-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000359524.7(RUNX2):​c.11C>T​(p.Pro4Leu) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RUNX2 ENST00000359524.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.11C>T	p.Pro4Leu	missense_variant	1/7		NP_001356334.1
RUNX2	NM_001278478.2	c.11C>T	p.Pro4Leu	missense_variant	1/6		NP_001265407.1
RUNX2	NM_001015051.4	c.59-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001015051.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2022

This variant has not been reported in the literature in individuals affected with RUNX2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 of the RUNX2 gene. It does not directly change the encoded amino acid sequence of the RUNX2 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PROVEAN	Uncertain	-3.1	D;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.76
MutPred		0.42		Gain of sheet (P = 0.0011);Gain of sheet (P = 0.0011);
MVP		0.88
ClinPred		0.98	D
GERP RS		2.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-45390324;