6-45544478-C-T

Variant names:

• chr6-45544478-C-T
• rs12333172
• NM_001024630.4:c.1022-739C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001024630.4(RUNX2):​c.1022-739C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,044 control chromosomes in the GnomAD database, including 2,198 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 0.15 (2198 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.36
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1022-739C>T		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.980-739C>T		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1022-2349C>T		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.980-2349C>T		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.1022-739C>T		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23039 AN: 151926 Hom.: 2199 Cov.: 32

Gnomad AFR AF: 0.0452

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.152 AC: 23038 AN: 152044 Hom.: 2198 Cov.: 32 AF XY: 0.152 AC XY: 11280 AN XY: 74304

African (AFR) AF: 0.0452 AC: 1876 AN: 41502

American (AMR) AF: 0.132 AC: 2016 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3466

East Asian (EAS) AF: 0.202 AC: 1043 AN: 5166

South Asian (SAS) AF: 0.132 AC: 634 AN: 4820

European-Finnish (FIN) AF: 0.240 AC: 2535 AN: 10546

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.201 AC: 13693 AN: 67964

Other (OTH) AF: 0.160 AC: 338 AN: 2106

Alfa AF: 0.151 Hom.: 1323

Bravo AF: 0.141

Asia WGS AF: 0.133 AC: 463 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.50
PhyloP100		3.4
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: rs12333172; hg19: chr6-45512215;