NM_001024630.4:c.243_260dupGGCGGCTGCGGCGGCGGC

Variant names:

Variant summary

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

The NM_001024630.4(RUNX2):c.243_260dupGGCGGCTGCGGCGGCGGC(p.Ala82_Ala87dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000529 in 1,531,164 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

RUNX2
NM_001024630.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.995

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:

Genome browser will be placed here

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 GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4 link	c.243_260dupGGCGGCTGCGGCGGCGGC	p.Ala82_Ala87dup	disruptive_inframe_insertion	Exon 3 of 9	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 link	c.201_218dupGGCGGCTGCGGCGGCGGC	p.Ala68_Ala73dup	disruptive_inframe_insertion	Exon 1 of 7		NP_001356334.1
RUNX2	NM_001015051.4 link	c.243_260dupGGCGGCTGCGGCGGCGGC	p.Ala82_Ala87dup	disruptive_inframe_insertion	Exon 3 of 8		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 link	c.201_218dupGGCGGCTGCGGCGGCGGC	p.Ala68_Ala73dup	disruptive_inframe_insertion	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.243_260dupGGCGGCTGCGGCGGCGGC	p.Ala82_Ala87dup	disruptive_inframe_insertion	Exon 3 of 9		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.0000794

AC:

AN:

151188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000738

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000500

AC:

AN:

1379866

Hom.:

Cov.:

AF XY:

0.0000496

AC XY:

AN XY:

685044

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

28594

American (AMR)

AF:

0.00

AC:

AN:

32990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23584

East Asian (EAS)

AF:

0.0000308

AC:

AN:

32500

South Asian (SAS)

AF:

0.0000265

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:

0.0000595

AC:

AN:

1075520

Other (OTH)

AF:

0.0000354

AC:

AN:

56492

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.368

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000793

AC:

AN:

151298

Hom.:

Cov.:

AF XY:

0.0000676

AC XY:

AN XY:

73922

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41330

American (AMR)

AF:

0.0000659

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.000197

AC:

AN:

5088

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000738

AC:

AN:

67730

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

134

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.243_260dup, results in the insertion of 6 amino acid(s) of the RUNX2 protein (p.Ala84_Ala89dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with RUNX2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

PhyloP100

0.99

Mutation Taster

=75/25

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over