6-45449381-T-C

Variant names:

• chr6-45449381-T-C
• rs765724
• NM_001024630.4:c.685+11330T>C

Variant summary

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

The NM_001024630.4(RUNX2):​c.685+11330T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 152,106 control chromosomes in the GnomAD database, including 40,101 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 0.72 (40101 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.862
• Publications: 7 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=-0.34).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.685+11330T>C		intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.643+11330T>C		intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.685+11330T>C		intron_variant	Intron 5 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.643+11330T>C		intron_variant	Intron 3 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.685+11330T>C		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109440 AN: 151988 Hom.: 40052 Cov.: 32

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.783

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.953

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.666

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.727

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

GnomAD4 genome AF: 0.720 AC: 109547 AN: 152106 Hom.: 40101 Cov.: 32 AF XY: 0.722 AC XY: 53725 AN XY: 74362

African (AFR) AF: 0.836 AC: 34702 AN: 41502

American (AMR) AF: 0.710 AC: 10849 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2089 AN: 3470

East Asian (EAS) AF: 0.953 AC: 4939 AN: 5180

South Asian (SAS) AF: 0.721 AC: 3460 AN: 4800

European-Finnish (FIN) AF: 0.666 AC: 7053 AN: 10590

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 43979 AN: 67956

Other (OTH) AF: 0.729 AC: 1541 AN: 2114

Alfa AF: 0.685 Hom.: 13991

Bravo AF: 0.729

Asia WGS AF: 0.833 AC: 2893 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.77
PhyloP100		0.86
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: rs765724; hg19: chr6-45417118;