6-45453311-G-C

Variant names:

• chr6-45453311-G-C
• rs2819863
• NM_001024630.4:c.685+15260G>C

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+15260G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.931 in 152,234 control chromosomes in the GnomAD database, including 66,116 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 0.93 (66116 hom., cov: 31)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.913
• Publications: 6 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 = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.685+15260G>C		intron_variant	Intron 5 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.643+15260G>C		intron_variant	Intron 3 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.685+15260G>C		intron_variant	Intron 5 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.643+15260G>C		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+15260G>C		intron_variant	Intron 5 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.931 AC: 141587 AN: 152116 Hom.: 66053 Cov.: 31

Gnomad AFR AF: 0.983

Gnomad AMI AF: 0.901

Gnomad AMR AF: 0.956

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.987

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.895

Gnomad OTH AF: 0.942

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

GnomAD4 genome AF: 0.931 AC: 141709 AN: 152234 Hom.: 66116 Cov.: 31 AF XY: 0.931 AC XY: 69302 AN XY: 74402

African (AFR) AF: 0.983 AC: 40843 AN: 41552

American (AMR) AF: 0.956 AC: 14623 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3173 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5153 AN: 5156

South Asian (SAS) AF: 0.988 AC: 4760 AN: 4820

European-Finnish (FIN) AF: 0.865 AC: 9173 AN: 10602

Middle Eastern (MID) AF: 0.983 AC: 289 AN: 294

European-Non Finnish (NFE) AF: 0.895 AC: 60880 AN: 68018

Other (OTH) AF: 0.943 AC: 1993 AN: 2114

Alfa AF: 0.874 Hom.: 1939

Bravo AF: 0.939

Asia WGS AF: 0.988 AC: 3433 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	0.57
DANN	Benign	0.48
PhyloP100		-0.91
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: rs2819863; hg19: chr6-45421048;