chr6-45422749-AGGCGGCGGCGGCGGCTGC-A

Variant names:

• chr6-45422749-AGGCGGCGGCGGCGGCTGC-A
• rs11498192
• NM_001024630.4:c.243_260delGGCGGCTGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001024630.4(RUNX2):​c.243_260delGGCGGCTGCGGCGGCGGC​(p.Ala82_Ala87del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0616 in 1,529,834 control chromosomes in the GnomAD database, including 9,156 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (191 hom., cov: 29)
  • Exomes 𝑓: 0.063 (8965 hom.)
• Consequence: RUNX2 NM_001024630.4 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.35
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001024630.4
• BP6: Variant 6-45422749-AGGCGGCGGCGGCGGCTGC-A is Benign according to our data. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in CliVar as Benign/Likely_benign. Clinvar id is 257095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.243_260delGGCGGCTGCGGCGGCGGC	p.Ala82_Ala87del	disruptive_inframe_deletion	Exon 3 of 9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.201_218delGGCGGCTGCGGCGGCGGC	p.Ala68_Ala73del	disruptive_inframe_deletion	Exon 1 of 7		NP_001356334.1
RUNX2	NM_001015051.4	c.243_260delGGCGGCTGCGGCGGCGGC	p.Ala82_Ala87del	disruptive_inframe_deletion	Exon 3 of 8		NP_001015051.3
RUNX2	NM_001278478.2	c.201_218delGGCGGCTGCGGCGGCGGC	p.Ala68_Ala73del	disruptive_inframe_deletion	Exon 1 of 6		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.243_260delGGCGGCTGCGGCGGCGGC	p.Ala82_Ala87del	disruptive_inframe_deletion	Exon 3 of 9		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6892 AN: 151130 Hom.: 191 Cov.: 29

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0468

Gnomad ASJ AF: 0.0588

Gnomad EAS AF: 0.0159

Gnomad SAS AF: 0.00937

Gnomad FIN AF: 0.0491

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0649

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.0638 AC: 10383 AN: 162630 AF XY: 0.0613

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.0670

Gnomad ASJ exome AF: 0.0814

Gnomad EAS exome AF: 0.0233

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0843

Gnomad OTH exome AF: 0.0858

GnomAD4 exome AF: 0.0633 AC: 87287 AN: 1378594 Hom.: 8965 AF XY: 0.0625 AC XY: 42802 AN XY: 684354

African (AFR) AF: 0.0214 AC: 611 AN: 28592

American (AMR) AF: 0.0618 AC: 2037 AN: 32978

Ashkenazi Jewish (ASJ) AF: 0.0741 AC: 1745 AN: 23548

East Asian (EAS) AF: 0.0257 AC: 834 AN: 32494

South Asian (SAS) AF: 0.0204 AC: 1540 AN: 75382

European-Finnish (FIN) AF: 0.0569 AC: 2811 AN: 49372

Middle Eastern (MID) AF: 0.0569 AC: 303 AN: 5324

European-Non Finnish (NFE) AF: 0.0688 AC: 73905 AN: 1074450

Other (OTH) AF: 0.0620 AC: 3501 AN: 56454

GnomAD4 genome AF: 0.0455 AC: 6884 AN: 151240 Hom.: 191 Cov.: 29 AF XY: 0.0438 AC XY: 3233 AN XY: 73890

African (AFR) AF: 0.0173 AC: 714 AN: 41318

American (AMR) AF: 0.0466 AC: 707 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.0588 AC: 203 AN: 3452

East Asian (EAS) AF: 0.0157 AC: 80 AN: 5088

South Asian (SAS) AF: 0.00896 AC: 43 AN: 4800

European-Finnish (FIN) AF: 0.0491 AC: 511 AN: 10416

Middle Eastern (MID) AF: 0.0548 AC: 16 AN: 292

European-Non Finnish (NFE) AF: 0.0649 AC: 4393 AN: 67704

Other (OTH) AF: 0.0451 AC: 94 AN: 2084

Alfa AF: 0.0375 Hom.: 134

Bravo AF: 0.0447

Asia WGS AF: 0.0160 AC: 56 AN: 3454

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jul 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:3

Nov 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 6 amino acids in a repetitive region with no known function; In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29960047, 29089101, 9182765, 28027977) -

Nov 01, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cleidocranial dysostosis Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=197/3	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs11498192; hg19: chr6-45390486; COSMIC: COSV61841096; COSMIC: COSV61841096;