rs10498760

Variant names:

• chr6-45396059-C-A
• rs10498760
• NM_001024630.4:c.59-26534C>A

Variant summary

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

The NM_001024630.4(RUNX2):​c.59-26534C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.074 in 152,142 control chromosomes in the GnomAD database, including 576 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 0.074 (576 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.659
• Publications: 6 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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-26534C>A		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001015051.4	c.59-26534C>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.59-26534C>A		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11270 AN: 152024 Hom.: 579 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.0510

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0958

Gnomad OTH AF: 0.0661

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

GnomAD4 genome AF: 0.0740 AC: 11265 AN: 152142 Hom.: 576 Cov.: 32 AF XY: 0.0775 AC XY: 5766 AN XY: 74358

African (AFR) AF: 0.0164 AC: 679 AN: 41526

American (AMR) AF: 0.0767 AC: 1173 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0510 AC: 177 AN: 3472

East Asian (EAS) AF: 0.0520 AC: 269 AN: 5176

South Asian (SAS) AF: 0.178 AC: 856 AN: 4812

European-Finnish (FIN) AF: 0.133 AC: 1400 AN: 10562

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0958 AC: 6511 AN: 67988

Other (OTH) AF: 0.0659 AC: 139 AN: 2110

Alfa AF: 0.0779 Hom.: 203

Bravo AF: 0.0646

Asia WGS AF: 0.100 AC: 345 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.99
DANN	Benign	0.61
PhyloP100		0.66
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: rs10498760; hg19: chr6-45363796;