rs10948237

Variant names:

• chr6-45539557-G-A
• rs10948237
• NM_001024630.4:c.1022-5660G>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.1022-5660G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,040 control chromosomes in the GnomAD database, including 17,400 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 0.46 (17400 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.572
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1022-5660G>A		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.980-5660G>A		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1022-7270G>A		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.980-7270G>A		intron_variant	Intron 5 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.1022-5660G>A		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70020 AN: 151922 Hom.: 17365 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.433

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

GnomAD4 genome AF: 0.461 AC: 70096 AN: 152040 Hom.: 17400 Cov.: 32 AF XY: 0.451 AC XY: 33539 AN XY: 74310

African (AFR) AF: 0.635 AC: 26315 AN: 41464

American (AMR) AF: 0.408 AC: 6245 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1549 AN: 3472

East Asian (EAS) AF: 0.0437 AC: 226 AN: 5174

South Asian (SAS) AF: 0.274 AC: 1320 AN: 4816

European-Finnish (FIN) AF: 0.369 AC: 3892 AN: 10552

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29220 AN: 67958

Other (OTH) AF: 0.428 AC: 903 AN: 2108

Alfa AF: 0.456 Hom.: 2011

Bravo AF: 0.471

Asia WGS AF: 0.186 AC: 651 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.070
DANN	Benign	0.50
PhyloP100		-0.57
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: rs10948237; hg19: chr6-45507294;