rs9296459

Variant names:

• chr6-45401060-G-A
• rs9296459
• NM_001024630.4:c.59-21533G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-45401060-G-A
• chr6-45401060-G-T

Variant summary

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

The NM_001024630.4(RUNX2):​c.59-21533G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 151,976 control chromosomes in the GnomAD database, including 6,052 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 0.26 (6052 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.719
• Publications: 10 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: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• 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 (NFE) allele frequency at 95% confidence interval = 0.346 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-21533G>A		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.59-21533G>A		intron_variant	Intron 2 of 7		NP_001015051.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-21533G>A		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38810 AN: 151858 Hom.: 6055 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.0756

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.255 AC: 38811 AN: 151976 Hom.: 6052 Cov.: 32 AF XY: 0.256 AC XY: 18994 AN XY: 74266

African (AFR) AF: 0.0947 AC: 3928 AN: 41458

American (AMR) AF: 0.233 AC: 3556 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 909 AN: 3466

East Asian (EAS) AF: 0.0758 AC: 393 AN: 5184

South Asian (SAS) AF: 0.298 AC: 1434 AN: 4818

European-Finnish (FIN) AF: 0.378 AC: 3975 AN: 10508

Middle Eastern (MID) AF: 0.271 AC: 79 AN: 292

European-Non Finnish (NFE) AF: 0.350 AC: 23783 AN: 67954

Other (OTH) AF: 0.247 AC: 523 AN: 2114

Alfa AF: 0.314 Hom.: 24588

Bravo AF: 0.236

Asia WGS AF: 0.172 AC: 599 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.94
DANN	Benign	0.79
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9296459; hg19: chr6-45368797;