rs774172072

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001024630.4(RUNX2):c.193_213delCAACAGCAGCAGCAGCAGCAG(p.Gln65_Gln71del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,601,344 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

RUNX2
NM_001024630.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 3.50

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001024630.4

BP6

Variant 6-45422693-ACAGCAGCAGCAGCAACAGCAG-A is Benign according to our data. Variant chr6-45422693-ACAGCAGCAGCAGCAACAGCAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196302.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00156 (237/151656) while in subpopulation NFE AF= 0.00255 (173/67814). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High AC in GnomAd4 at 237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4 linkuse as main transcript	c.193_213delCAACAGCAGCAGCAGCAGCAG	p.Gln65_Gln71del	conservative_inframe_deletion	3/9	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 linkuse as main transcript	c.151_171delCAACAGCAGCAGCAGCAGCAG	p.Gln51_Gln57del	conservative_inframe_deletion	1/7		NP_001356334.1
RUNX2	NM_001015051.4 linkuse as main transcript	c.193_213delCAACAGCAGCAGCAGCAGCAG	p.Gln65_Gln71del	conservative_inframe_deletion	3/8		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 linkuse as main transcript	c.151_171delCAACAGCAGCAGCAGCAGCAG	p.Gln51_Gln57del	conservative_inframe_deletion	1/6		NP_001265407.1	Q32MY8A0A0D9SEN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2 linkuse as main transcript	c.193_213delCAACAGCAGCAGCAGCAGCAG	p.Gln65_Gln71del	conservative_inframe_deletion	3/9		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

237

AN:

151552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000993

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000390

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.000665

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00255

Gnomad OTH

AF:

0.000961

GnomAD3 exomes

AF:

0.00104

AC:

242

AN:

232308

Hom.:

AF XY:

0.00108

AC XY:

138

AN XY:

128068

show subpopulations

Gnomad AFR exome

AF:

0.000232

Gnomad AMR exome

AF:

0.000684

Gnomad ASJ exome

AF:

0.000104

Gnomad EAS exome

AF:

0.000664

Gnomad SAS exome

AF:

0.000347

Gnomad FIN exome

AF:

0.000659

Gnomad NFE exome

AF:

0.00170

Gnomad OTH exome

AF:

0.000361

GnomAD4 exome

AF:

0.00139

AC:

2011

AN:

1449688

Hom.:

AF XY:

0.00144

AC XY:

1040

AN XY:

720976

show subpopulations

Gnomad4 AFR exome

AF:

0.000552

Gnomad4 AMR exome

AF:

0.000669

Gnomad4 ASJ exome

AF:

0.000116

Gnomad4 EAS exome

AF:

0.000856

Gnomad4 SAS exome

AF:

0.000403

Gnomad4 FIN exome

AF:

0.00150

Gnomad4 NFE exome

AF:

0.00155

Gnomad4 OTH exome

AF:

0.00165

GnomAD4 genome

AF:

0.00156

AC:

237

AN:

151656

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

AN XY:

74122

show subpopulations

Gnomad4 AFR

AF:

0.000990

Gnomad4 AMR

AF:

0.000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000391

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.000665

Gnomad4 NFE

AF:

0.00255

Gnomad4 OTH

AF:

0.000951

Alfa

AF:

0.00129

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This variant, c.193_213del, results in the deletion of 7 amino acid(s) of the RUNX2 protein (p.Gln65_Gln71del), 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. ClinVar contains an entry for this variant (Variation ID: 196302). 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RUNX2: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	In-frame deletion in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over