6-45428582-A-T

Variant names:

• chr6-45428582-A-T
• rs2819858
• NM_001024630.4:c.424-3281A>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.424-3281A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 151,944 control chromosomes in the GnomAD database, including 15,851 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 0.45 (15851 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.244
• Publications: 3 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.424-3281A>T		intron_variant	Intron 3 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.382-3281A>T		intron_variant	Intron 1 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.424-3281A>T		intron_variant	Intron 3 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.382-3281A>T		intron_variant	Intron 1 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.424-3281A>T		intron_variant	Intron 3 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68953 AN: 151826 Hom.: 15841 Cov.: 32

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.607

Gnomad FIN AF: 0.504

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.454 AC: 68995 AN: 151944 Hom.: 15851 Cov.: 32 AF XY: 0.458 AC XY: 34009 AN XY: 74246

African (AFR) AF: 0.392 AC: 16212 AN: 41384

American (AMR) AF: 0.425 AC: 6502 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1631 AN: 3470

East Asian (EAS) AF: 0.572 AC: 2957 AN: 5174

South Asian (SAS) AF: 0.608 AC: 2927 AN: 4816

European-Finnish (FIN) AF: 0.504 AC: 5312 AN: 10548

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31935 AN: 67950

Other (OTH) AF: 0.460 AC: 966 AN: 2102

Alfa AF: 0.461 Hom.: 1976

Bravo AF: 0.440

Asia WGS AF: 0.579 AC: 2012 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.9
DANN	Benign	0.61
PhyloP100		0.24
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: rs2819858; hg19: chr6-45396319;