rs781355841

Positions:

• chr6-45422681-ACAGCAGCAGCAACAG-A
• chr6-45422681-ACAGCAGCAGCAACAG-ACAGCAGCAGCAACAGCAGCAGCAGCAACAG

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001024630.4(RUNX2):​c.174_188del​(p.Gln67_Gln71del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,602,446 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: RUNX2 NM_001024630.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000191 (29/151556) while in subpopulation SAS AF= 0.00167 (8/4786). AF 95% confidence interval is 0.000831. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.174_188del	p.Gln67_Gln71del	inframe_deletion	3/9	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.174_188del	p.Gln67_Gln71del	inframe_deletion	3/8		NP_001015051.3
RUNX2	NM_001278478.2	c.132_146del	p.Gln53_Gln57del	inframe_deletion	1/6		NP_001265407.1
RUNX2	NM_001369405.1	c.132_146del	p.Gln53_Gln57del	inframe_deletion	1/7		NP_001356334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.174_188del	p.Gln67_Gln71del	inframe_deletion	3/9		NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes AF: 0.000185 AC: 28 AN: 151444 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000194 AC: 46 AN: 236718 Hom.: 0 AF XY: 0.000238 AC XY: 31 AN XY: 130112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.00106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000169 AC: 245 AN: 1450890 Hom.: 1 AF XY: 0.000204 AC XY: 147 AN XY: 721656

Gnomad4 AFR exome AF: 0.000213

Gnomad4 AMR exome AF: 0.0000461

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.000191 AC: 29 AN: 151556 Hom.: 0 Cov.: 30 AF XY: 0.000149 AC XY: 11 AN XY: 74064

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000392

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000240 Hom.: 0

Asia WGS AF: 0.000867 AC: 3 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2023

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, c.174_188del, results in the deletion of 5 amino acid(s) of the RUNX2 protein (p.Gln67_Gln71del), but otherwise preserves the integrity of the reading frame. This variant has not been reported in the literature in individuals affected with RUNX2-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 845536). -

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: rs781355841; hg19: chr6-45390418;