6-45544478-C-T

Position:

• chr6-45544478-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001024630.4(RUNX2):​c.1022-739C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,044 control chromosomes in the GnomAD database, including 2,198 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 0.15 (2198 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1022-739C>T		intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.1022-2349C>T		intron_variant			NP_001015051.3
RUNX2	NM_001278478.2	c.980-2349C>T		intron_variant			NP_001265407.1
RUNX2	NM_001369405.1	c.980-739C>T		intron_variant			NP_001356334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.1022-739C>T		intron_variant			NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23039 AN: 151926 Hom.: 2199 Cov.: 32

Gnomad AFR AF: 0.0452

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.152 AC: 23038 AN: 152044 Hom.: 2198 Cov.: 32 AF XY: 0.152 AC XY: 11280 AN XY: 74304

Gnomad4 AFR AF: 0.0452

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.240

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.160

Alfa AF: 0.163 Hom.: 741

Bravo AF: 0.141

Asia WGS AF: 0.133 AC: 463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs12333172; hg19: chr6-45512215;