6-45552293-A-T

Position:

• chr6-45552293-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000576263.5	c.1021+39886A>T		intron_variant		5		ENSP00000458178
RUNX2	ENST00000478660.6	c.*178+38640A>T		intron_variant, NMD_transcript_variant		5		ENSP00000460188

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

Gnomad4 AFR AF: 0.516

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.370

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.385

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.80
DANN	Benign	0.42

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs598953; hg19: chr6-45520030;