6-45436037-C-T

Variant names:

• chr6-45436037-C-T
• rs2677108
• NM_001024630.4:c.581-1910C>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.581-1910C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 151,974 control chromosomes in the GnomAD database, including 24,429 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 0.56 (24429 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.574
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, Orphanet
• 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=-0.6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.581-1910C>T		intron	N/A	NP_001019801.3	Q13950-1
	RUNX2	NM_001369405.1		c.539-1910C>T		intron	N/A	NP_001356334.1	Q13950-2
	RUNX2	NM_001015051.4		c.581-1910C>T		intron	N/A	NP_001015051.3	Q13950-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.581-1910C>T		intron	N/A	ENSP00000495497.1	Q13950-1
	RUNX2	ENST00000359524.7	TSL:1	c.539-1910C>T		intron	N/A	ENSP00000352514.5	Q13950-2
	RUNX2	ENST00000625924.1	TSL:1	c.539-1910C>T		intron	N/A	ENSP00000485863.1	A0A0D9SEN7

Frequencies

GnomAD3 genomes AF: 0.558 AC: 84664 AN: 151856 Hom.: 24423 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.570

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.792

Gnomad FIN AF: 0.734

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.561

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

GnomAD4 genome AF: 0.557 AC: 84694 AN: 151974 Hom.: 24429 Cov.: 32 AF XY: 0.567 AC XY: 42108 AN XY: 74298

African (AFR) AF: 0.411 AC: 17012 AN: 41424

American (AMR) AF: 0.535 AC: 8170 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1929 AN: 3472

East Asian (EAS) AF: 0.627 AC: 3234 AN: 5160

South Asian (SAS) AF: 0.791 AC: 3818 AN: 4824

European-Finnish (FIN) AF: 0.734 AC: 7745 AN: 10558

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.602 AC: 40895 AN: 67942

Other (OTH) AF: 0.565 AC: 1193 AN: 2112

Alfa AF: 0.584 Hom.: 48152

Bravo AF: 0.530

Asia WGS AF: 0.683 AC: 2373 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.2
DANN	Benign	0.83
PhyloP100		0.57
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: rs2677108; hg19: chr6-45403774;