Genetic Variant NM_001024630.4:c.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC (chr6-45422749-AGGCGGCGGCGGCGGCTGCGGCGGCGGCGGCGGCTGC-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS2

The NM_001024630.4(RUNX2):c.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC(p.Ala76_Ala87del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000362 in 1,379,934 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A75A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0000036 ( 1 hom. )

Consequence

RUNX2
NM_001024630.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.35

Publications

6 publications found

Variant links:

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

RUNX2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001024630.4

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4 link	c.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala76_Ala87del	disruptive_inframe_deletion	Exon 3 of 9	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 link	c.183_218delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala62_Ala73del	disruptive_inframe_deletion	Exon 1 of 7		NP_001356334.1
RUNX2	NM_001015051.4 link	c.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala76_Ala87del	disruptive_inframe_deletion	Exon 3 of 8		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 link	c.183_218delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala62_Ala73del	disruptive_inframe_deletion	Exon 1 of 6		NP_001265407.1	Q32MY8A0A0D9SEN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 link	c.225_260delGGCGGCTGCGGCGGCGGCGGCGGCTGCGGCGGCGGC	p.Ala76_Ala87del	disruptive_inframe_deletion	Exon 3 of 9		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000246

AC:

AN:

162630

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000362

AC:

AN:

1379934

Hom.:

AF XY:

0.00

AC XY:

AN XY:

685076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28596

American (AMR)

AF:

0.00

AC:

AN:

32990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23584

East Asian (EAS)

AF:

0.0000615

AC:

AN:

32500

South Asian (SAS)

AF:

0.0000133

AC:

AN:

75430

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075584

Other (OTH)

AF:

0.0000177

AC:

AN:

56494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.758

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Mutation Taster

=192/8

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over