6-45552293-A-T

Variant names:

• chr6-45552293-A-T
• rs598953
• ENST00000576263.5:c.1021+39886A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000576263.5(RUNX2):​c.1021+39886A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 151,956 control chromosomes in the GnomAD database, including 12,995 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (12995 hom., cov: 32)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.135
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, Orphanet
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000576263.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000576263.5	TSL:5	c.1021+39886A>T		intron	N/A	ENSP00000458178.1	I3L0L0
	RUNX2	ENST00000478660.6	TSL:5	n.*178+38640A>T		intron	N/A	ENSP00000460188.1	I3L354

Frequencies

GnomAD3 genomes AF: 0.409 AC: 62071 AN: 151836 Hom.: 12972 Cov.: 32

Gnomad AFR AF: 0.515

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.370

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.389

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.409 AC: 62133 AN: 151956 Hom.: 12995 Cov.: 32 AF XY: 0.407 AC XY: 30188 AN XY: 74240

African (AFR) AF: 0.516 AC: 21386 AN: 41444

American (AMR) AF: 0.371 AC: 5670 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.370 AC: 1284 AN: 3470

East Asian (EAS) AF: 0.234 AC: 1210 AN: 5162

South Asian (SAS) AF: 0.348 AC: 1678 AN: 4816

European-Finnish (FIN) AF: 0.372 AC: 3910 AN: 10522

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25856 AN: 67950

Other (OTH) AF: 0.385 AC: 813 AN: 2110

Alfa AF: 0.404 Hom.: 1587

Bravo AF: 0.413

Asia WGS AF: 0.277 AC: 965 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.80
DANN	Benign	0.42
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs598953; hg19: chr6-45520030;