Genetic Variant RUNX2:c.685+15260G>T (chr6-45453311-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2BP4_StrongBS2

The NM_001024630.4(RUNX2):c.685+15260G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 152,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Consequence

RUNX2
NM_001024630.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.913

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 -6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4 link	c.685+15260G>T	intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 link	c.643+15260G>T	intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4 link	c.685+15260G>T	intron_variant	Intron 5 of 7		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 link	c.643+15260G>T	intron_variant	Intron 3 of 5		NP_001265407.1	Q32MY8A0A0D9SEN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 link	c.685+15260G>T		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41556

American (AMR)

AF:

0.000262

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

1939

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.54

(source)

DANN

Benign

0.19

PhyloP100

-0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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