6-45436791-A-G

Variant names:

• chr6-45436791-A-G
• rs2819854
• NM_001024630.4:c.581-1156A>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.581-1156A>G variant causes a intron change. The variant allele was found at a frequency of 0.49 in 152,038 control chromosomes in the GnomAD database, including 18,610 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 0.49 (18610 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17
• Publications: 8 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=-0.51).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.581-1156A>G		intron_variant	Intron 4 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.539-1156A>G		intron_variant	Intron 2 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.581-1156A>G		intron_variant	Intron 4 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.539-1156A>G		intron_variant	Intron 2 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.581-1156A>G		intron_variant	Intron 4 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74517 AN: 151920 Hom.: 18599 Cov.: 32

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.504

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

GnomAD4 genome AF: 0.490 AC: 74550 AN: 152038 Hom.: 18610 Cov.: 32 AF XY: 0.494 AC XY: 36688 AN XY: 74320

African (AFR) AF: 0.393 AC: 16299 AN: 41464

American (AMR) AF: 0.486 AC: 7414 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1785 AN: 3470

East Asian (EAS) AF: 0.612 AC: 3162 AN: 5168

South Asian (SAS) AF: 0.624 AC: 3003 AN: 4812

European-Finnish (FIN) AF: 0.552 AC: 5827 AN: 10556

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35331 AN: 67986

Other (OTH) AF: 0.507 AC: 1070 AN: 2110

Alfa AF: 0.507 Hom.: 68387

Bravo AF: 0.480

Asia WGS AF: 0.598 AC: 2080 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.86
PhyloP100		4.2
Mutation Taster		=97/3	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: rs2819854; hg19: chr6-45404528;