chr6-45518470-C-G

Position:

• chr6-45518470-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):​c.1021+6063C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 151,844 control chromosomes in the GnomAD database, including 12,306 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 0.38 (12306 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.616

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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1021+6063C>G		intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.1021+6063C>G		intron_variant			NP_001015051.3
RUNX2	NM_001278478.2	c.979+6063C>G		intron_variant			NP_001265407.1
RUNX2	NM_001369405.1	c.979+6063C>G		intron_variant			NP_001356334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.1021+6063C>G		intron_variant			NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes AF: 0.379 AC: 57527 AN: 151726 Hom.: 12292 Cov.: 32

Gnomad AFR AF: 0.602

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.299

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.287

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.379 AC: 57574 AN: 151844 Hom.: 12306 Cov.: 32 AF XY: 0.378 AC XY: 28011 AN XY: 74184

Gnomad4 AFR AF: 0.602

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.299

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.282

Gnomad4 NFE AF: 0.287

Gnomad4 OTH AF: 0.325

Alfa AF: 0.207 Hom.: 428

Bravo AF: 0.394

Asia WGS AF: 0.266 AC: 929 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.75

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: rs7771889; hg19: chr6-45486207;