chr6-45422749-AGGCGGCGGCGGCGGCTGC-A

Position:

• chr6-45422749-AGGCGGCGGCGGCGGCTGC-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The NM_001024630.4(RUNX2):​c.243_260del​(p.Ala84_Ala89del) variant causes a 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. 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 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.35

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]

ACMG classification

Verdict is Benign. Variant got -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 ClinVar as [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 Lovd as [Benign]. Variant chr6-45422749-AGGCGGCGGCGGCGGCTGC-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.243_260del	p.Ala84_Ala89del	inframe_deletion	3/9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.243_260del	p.Ala84_Ala89del	inframe_deletion	3/8		NP_001015051.3
RUNX2	NM_001278478.2	c.201_218del	p.Ala70_Ala75del	inframe_deletion	1/6		NP_001265407.1
RUNX2	NM_001369405.1	c.201_218del	p.Ala70_Ala75del	inframe_deletion	1/7		NP_001356334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.243_260del	p.Ala84_Ala89del	inframe_deletion	3/9		NM_001024630.4	ENSP00000495497	P4

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

GnomAD3 exomes AF: 0.0638 AC: 10383 AN: 162630 Hom.: 2097 AF XY: 0.0613 AC XY: 5666 AN XY: 92448

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 SAS exome AF: 0.0221

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

Gnomad4 AFR exome AF: 0.0214

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0741

Gnomad4 EAS exome AF: 0.0257

Gnomad4 SAS exome AF: 0.0204

Gnomad4 FIN exome AF: 0.0569

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0620

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

Gnomad4 AFR AF: 0.0173

Gnomad4 AMR AF: 0.0466

Gnomad4 ASJ AF: 0.0588

Gnomad4 EAS AF: 0.0157

Gnomad4 SAS AF: 0.00896

Gnomad4 FIN AF: 0.0491

Gnomad4 NFE AF: 0.0649

Gnomad4 OTH AF: 0.0451

Bravo AF: 0.0447

Asia WGS AF: 0.0160 AC: 56 AN: 3454

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 25, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	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) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

Cleidocranial dysostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11498192; hg19: chr6-45390486;