rs1406846

Variant names:

• chr6-45433203-T-A
• rs1406846
• NM_001024630.4:c.580+1184T>A

Your query was ambiguous. Multiple possible variants found:

• chr6-45433203-T-A
• chr6-45433203-T-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001024630.4(RUNX2):​c.580+1184T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.5 in 151,972 control chromosomes in the GnomAD database, including 19,059 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 0.50 (19059 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.580+1184T>A		intron_variant	Intron 4 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.538+1184T>A		intron_variant	Intron 2 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.580+1184T>A		intron_variant	Intron 4 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.538+1184T>A		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.580+1184T>A		intron_variant	Intron 4 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75911 AN: 151854 Hom.: 19045 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.534

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.507

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

GnomAD4 genome AF: 0.500 AC: 75973 AN: 151972 Hom.: 19059 Cov.: 32 AF XY: 0.503 AC XY: 37400 AN XY: 74288

African (AFR) AF: 0.473 AC: 19610 AN: 41440

American (AMR) AF: 0.458 AC: 7001 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1751 AN: 3472

East Asian (EAS) AF: 0.576 AC: 2977 AN: 5164

South Asian (SAS) AF: 0.616 AC: 2965 AN: 4814

European-Finnish (FIN) AF: 0.543 AC: 5739 AN: 10564

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.504 AC: 34213 AN: 67922

Other (OTH) AF: 0.511 AC: 1080 AN: 2114

Alfa AF: 0.501 Hom.: 2350

Bravo AF: 0.489

Asia WGS AF: 0.590 AC: 2047 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.87
PhyloP100		2.0
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: rs1406846; hg19: chr6-45400940;