rs6921145

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001024630.4(RUNX2):c.240G>A(p.Ala80Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,487,112 control chromosomes in the GnomAD database, including 8,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 711 hom., cov: 31)

Exomes 𝑓: 0.10 ( 8082 hom. )

Consequence

RUNX2
NM_001024630.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.758

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 6-45422774-G-A is Benign according to our data. Variant chr6-45422774-G-A is described in ClinVar as [Benign]. Clinvar id is 196301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422774-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.758 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4 linkuse as main transcript	c.240G>A	p.Ala80Ala	synonymous_variant	3/9	ENST00000647337.2	NP_001019801.3	Q13950-1
RUNX2	NM_001369405.1 linkuse as main transcript	c.198G>A	p.Ala66Ala	synonymous_variant	1/7		NP_001356334.1
RUNX2	NM_001015051.4 linkuse as main transcript	c.240G>A	p.Ala80Ala	synonymous_variant	3/8		NP_001015051.3	Q13950-3
RUNX2	NM_001278478.2 linkuse as main transcript	c.198G>A	p.Ala66Ala	synonymous_variant	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.240G>A	p.Ala80Ala	synonymous_variant	3/9		NM_001024630.4	ENSP00000495497.1		Q13950-1

Frequencies

GnomAD3 genomes

AF:

0.0801

AC:

12115

AN:

151292

Hom.:

714

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0166

Gnomad AMI

AF:

0.0363

Gnomad AMR

AF:

0.0825

Gnomad ASJ

AF:

0.0511

Gnomad EAS

AF:

0.0553

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.190

Gnomad MID

AF:

0.0987

Gnomad NFE

AF:

0.0980

Gnomad OTH

AF:

0.0705

GnomAD3 exomes

AF:

0.133

AC:

16498

AN:

123672

Hom.:

1205

AF XY:

0.138

AC XY:

9827

AN XY:

71258

show subpopulations

Gnomad AFR exome

AF:

0.0204

Gnomad AMR exome

AF:

0.0970

Gnomad ASJ exome

AF:

0.0469

Gnomad EAS exome

AF:

0.0861

Gnomad SAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.188

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.104

AC:

138713

AN:

1335712

Hom.:

8082

Cov.:

AF XY:

0.107

AC XY:

70581

AN XY:

661156

show subpopulations

Gnomad4 AFR exome

AF:

0.0135

Gnomad4 AMR exome

AF:

0.0868

Gnomad4 ASJ exome

AF:

0.0471

Gnomad4 EAS exome

AF:

0.0861

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.180

Gnomad4 NFE exome

AF:

0.0992

Gnomad4 OTH exome

AF:

0.0918

GnomAD4 genome

AF:

0.0800

AC:

12109

AN:

151400

Hom.:

711

Cov.:

AF XY:

0.0860

AC XY:

6365

AN XY:

74002

show subpopulations

Gnomad4 AFR

AF:

0.0165

Gnomad4 AMR

AF:

0.0824

Gnomad4 ASJ

AF:

0.0511

Gnomad4 EAS

AF:

0.0555

Gnomad4 SAS

AF:

0.181

Gnomad4 FIN

AF:

0.190

Gnomad4 NFE

AF:

0.0980

Gnomad4 OTH

AF:

0.0703

Alfa

AF:

0.0562

Hom.:

Bravo

AF:

0.0668

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 09, 2014	- -

Cleidocranial dysostosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.97

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

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