6-45525346-C-T

Variant names:

• chr6-45525346-C-T
• rs6904353
• NM_001024630.4:c.1021+12939C>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.1021+12939C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 152,058 control chromosomes in the GnomAD database, including 18,636 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 0.47 (18636 hom., cov: 33)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• Publications: 5 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1021+12939C>T		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.979+12939C>T		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1021+12939C>T		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.979+12939C>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.1021+12939C>T		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.474 AC: 72004 AN: 151940 Hom.: 18594 Cov.: 33

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.445

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

GnomAD4 genome AF: 0.474 AC: 72091 AN: 152058 Hom.: 18636 Cov.: 33 AF XY: 0.464 AC XY: 34466 AN XY: 74340

African (AFR) AF: 0.675 AC: 28000 AN: 41458

American (AMR) AF: 0.414 AC: 6330 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.446 AC: 1546 AN: 3466

East Asian (EAS) AF: 0.0434 AC: 225 AN: 5180

South Asian (SAS) AF: 0.277 AC: 1336 AN: 4826

European-Finnish (FIN) AF: 0.369 AC: 3895 AN: 10566

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29402 AN: 67964

Other (OTH) AF: 0.440 AC: 929 AN: 2110

Alfa AF: 0.436 Hom.: 8043

Bravo AF: 0.486

Asia WGS AF: 0.187 AC: 654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.36
DANN	Benign	0.27
PhyloP100		-0.29
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: rs6904353; hg19: chr6-45493083;