chr6-45422753-G-GGCGGCGGCGGCTGCGGCGGCGGCGGCGGCT

Position:

• chr6-45422753-G-GGCGGCGGCGGCTGCGGCGGCGGCGGCGGCT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP3

The NM_001024630.4(RUNX2):​c.231_260dupTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC​(p.Ala78_Ala87dup) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RUNX2 NM_001024630.4 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.35

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-45422753-G-GGCGGCGGCGGCTGCGGCGGCGGCGGCGGCT is Pathogenic according to our data. Variant chr6-45422753-G-GGCGGCGGCGGCTGCGGCGGCGGCGGCGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 9297.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001024630.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.231_260dupTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala78_Ala87dup	disruptive_inframe_insertion	3/9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.189_218dupTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala64_Ala73dup	disruptive_inframe_insertion	1/7		NP_001356334.1
RUNX2	NM_001015051.4	c.231_260dupTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala78_Ala87dup	disruptive_inframe_insertion	3/8		NP_001015051.3
RUNX2	NM_001278478.2	c.189_218dupTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala64_Ala73dup	disruptive_inframe_insertion	1/6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.231_260dupTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala78_Ala87dup	disruptive_inframe_insertion	3/9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cleidocranial dysplasia 1, forme fruste, with brachydactyly Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 30, 1997

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231174; hg19: chr6-45390490;