6-45457203-A-G

Variant names:

• chr6-45457203-A-G
• rs2819861
• NM_001024630.4:c.685+19152A>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.685+19152A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 152,114 control chromosomes in the GnomAD database, including 42,098 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 0.74 (42098 hom., cov: 31)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.158
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.685+19152A>G		intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.643+19152A>G		intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.685+19152A>G		intron_variant	Intron 5 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.643+19152A>G		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+19152A>G		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111809 AN: 151996 Hom.: 42033 Cov.: 31

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.750

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.958

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.649

Gnomad OTH AF: 0.737

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

GnomAD4 genome AF: 0.736 AC: 111934 AN: 152114 Hom.: 42098 Cov.: 31 AF XY: 0.738 AC XY: 54881 AN XY: 74344

African (AFR) AF: 0.882 AC: 36588 AN: 41504

American (AMR) AF: 0.715 AC: 10923 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2096 AN: 3472

East Asian (EAS) AF: 0.958 AC: 4963 AN: 5180

South Asian (SAS) AF: 0.730 AC: 3521 AN: 4824

European-Finnish (FIN) AF: 0.687 AC: 7257 AN: 10564

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.649 AC: 44115 AN: 67982

Other (OTH) AF: 0.739 AC: 1559 AN: 2110

Alfa AF: 0.682 Hom.: 44166

Bravo AF: 0.745

Asia WGS AF: 0.846 AC: 2939 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.80
DANN	Benign	0.40
PhyloP100		0.16
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: rs2819861; hg19: chr6-45424940;