rs1321075

Variant names:

• chr6-45424206-T-G
• rs1321075
• NM_001024630.4:c.423+1249T>G

Variant summary

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

The NM_001024630.4(RUNX2):​c.423+1249T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.839 in 152,128 control chromosomes in the GnomAD database, including 53,691 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 0.84 (53691 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560
• Publications: 13 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=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.423+1249T>G		intron_variant	Intron 3 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.381+1249T>G		intron_variant	Intron 1 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.423+1249T>G		intron_variant	Intron 3 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.381+1249T>G		intron_variant	Intron 1 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.423+1249T>G		intron_variant	Intron 3 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127534 AN: 152012 Hom.: 53637 Cov.: 32

Gnomad AFR AF: 0.835

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.933

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.853

Gnomad OTH AF: 0.818

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

GnomAD4 genome AF: 0.839 AC: 127645 AN: 152128 Hom.: 53691 Cov.: 32 AF XY: 0.841 AC XY: 62556 AN XY: 74386

African (AFR) AF: 0.835 AC: 34687 AN: 41534

American (AMR) AF: 0.755 AC: 11548 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.771 AC: 2670 AN: 3464

East Asian (EAS) AF: 0.749 AC: 3828 AN: 5112

South Asian (SAS) AF: 0.934 AC: 4509 AN: 4830

European-Finnish (FIN) AF: 0.917 AC: 9721 AN: 10600

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.853 AC: 57986 AN: 67980

Other (OTH) AF: 0.820 AC: 1733 AN: 2114

Alfa AF: 0.839 Hom.: 188459

Bravo AF: 0.821

Asia WGS AF: 0.835 AC: 2905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.8
DANN	Benign	0.64
PhyloP100		0.056
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: rs1321075; hg19: chr6-45391943;