6-45422591-A-G

Position:

• chr6-45422591-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001024630.4(RUNX2):​c.59-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RUNX2 NM_001024630.4 splice_acceptor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.15

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.9, offset of 40, new splice context is: ttcagccccccctccagcAGcct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-45422591-A-G is Pathogenic according to our data. Variant chr6-45422591-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2729445.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	c.59-2A>G		splice_acceptor_variant, intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.15A>G	p.Val5Val	synonymous_variant	1/7		NP_001356334.1
RUNX2	NM_001278478.2	c.15A>G	p.Val5Val	synonymous_variant	1/6		NP_001265407.1
RUNX2	NM_001015051.4	c.59-2A>G		splice_acceptor_variant, intron_variant			NP_001015051.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-2A>G		splice_acceptor_variant, intron_variant			NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2023

This sequence change affects an acceptor splice site in intron 2 of the RUNX2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RUNX2 are known to be pathogenic (PMID: 10521292, 11857736). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RUNX2-related conditions. 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 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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	26
DANN	Benign	0.92
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.86		Position offset: 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: chr6-45390328; COSMIC: COSV61840680; COSMIC: COSV61840680;