rs2396442

Positions:

• chr6-45489244-T-C

Variant summary

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

The NM_001024630.4(RUNX2):​c.686-2697T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,098 control chromosomes in the GnomAD database, including 6,284 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 0.27 (6284 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.357

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.686-2697T>C		intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.644-2697T>C		intron_variant			NP_001356334.1
RUNX2	NM_001015051.4	c.686-2697T>C		intron_variant			NP_001015051.3
RUNX2	NM_001278478.2	c.644-2697T>C		intron_variant			NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.686-2697T>C		intron_variant			NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41702 AN: 151980 Hom.: 6283 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.0568

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.274 AC: 41697 AN: 152098 Hom.: 6284 Cov.: 32 AF XY: 0.272 AC XY: 20243 AN XY: 74316

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.289

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.0562

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.269

Alfa AF: 0.305 Hom.: 1505

Bravo AF: 0.267

Asia WGS AF: 0.159 AC: 555 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.5
DANN	Benign	0.58

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: rs2396442; hg19: chr6-45456981;