rs2819853

Variant names:

• chr6-45444920-G-A
• rs2819853
• NM_001024630.4:c.685+6869G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-45444920-G-A
• chr6-45444920-G-C
• chr6-45444920-G-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+6869G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.735 in 152,122 control chromosomes in the GnomAD database, including 41,944 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 (41944 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.95
• 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=-0.95).
• 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+6869G>A		intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.643+6869G>A		intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.685+6869G>A		intron_variant	Intron 5 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.643+6869G>A		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+6869G>A		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.734 AC: 111609 AN: 152004 Hom.: 41879 Cov.: 32

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.604

Gnomad EAS AF: 0.957

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.667

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.648

Gnomad OTH AF: 0.737

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

GnomAD4 genome AF: 0.735 AC: 111734 AN: 152122 Hom.: 41944 Cov.: 32 AF XY: 0.736 AC XY: 54727 AN XY: 74352

African (AFR) AF: 0.883 AC: 36646 AN: 41520

American (AMR) AF: 0.715 AC: 10931 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 2094 AN: 3468

East Asian (EAS) AF: 0.958 AC: 4959 AN: 5178

South Asian (SAS) AF: 0.734 AC: 3546 AN: 4828

European-Finnish (FIN) AF: 0.667 AC: 7037 AN: 10556

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.648 AC: 44054 AN: 67978

Other (OTH) AF: 0.739 AC: 1555 AN: 2104

Alfa AF: 0.700 Hom.: 6335

Bravo AF: 0.745

Asia WGS AF: 0.848 AC: 2945 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.0030
DANN	Benign	0.53
PhyloP100		-2.9
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: rs2819853; hg19: chr6-45412657;