6-45453893-C-T

Variant names:

• chr6-45453893-C-T
• rs1343799
• NM_001024630.4:c.685+15842C>T

Variant summary

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

The NM_001024630.4(RUNX2):​c.685+15842C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 152,184 control chromosomes in the GnomAD database, including 41,938 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 0.73 (41938 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.842
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.685+15842C>T		intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.643+15842C>T		intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.685+15842C>T		intron_variant	Intron 5 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.643+15842C>T		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+15842C>T		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111612 AN: 152066 Hom.: 41870 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.714

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.735

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

GnomAD4 genome AF: 0.734 AC: 111740 AN: 152184 Hom.: 41938 Cov.: 32 AF XY: 0.736 AC XY: 54758 AN XY: 74400

African (AFR) AF: 0.882 AC: 36621 AN: 41540

American (AMR) AF: 0.714 AC: 10927 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2090 AN: 3472

East Asian (EAS) AF: 0.958 AC: 4968 AN: 5188

South Asian (SAS) AF: 0.730 AC: 3525 AN: 4828

European-Finnish (FIN) AF: 0.668 AC: 7063 AN: 10580

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44048 AN: 67964

Other (OTH) AF: 0.738 AC: 1558 AN: 2112

Alfa AF: 0.700 Hom.: 15367

Bravo AF: 0.744

Asia WGS AF: 0.847 AC: 2942 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.20
DANN	Benign	0.29
PhyloP100		-0.84
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: rs1343799; hg19: chr6-45421630;