chr6-45543804-C-T

Variant names:

• chr6-45543804-C-T
• rs10948238
• NM_001024630.4:c.1022-1413C>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.1022-1413C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.455 in 151,660 control chromosomes in the GnomAD database, including 17,577 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 0.46 (17577 hom., cov: 30)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.744
• 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: 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1022-1413C>T		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.980-1413C>T		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1022-3023C>T		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.980-3023C>T		intron_variant	Intron 5 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.1022-1413C>T		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.455 AC: 68952 AN: 151540 Hom.: 17535 Cov.: 30

Gnomad AFR AF: 0.686

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.397

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.0437

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.327

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.433

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

GnomAD4 genome AF: 0.455 AC: 69036 AN: 151660 Hom.: 17577 Cov.: 30 AF XY: 0.445 AC XY: 32954 AN XY: 74078

African (AFR) AF: 0.686 AC: 28328 AN: 41292

American (AMR) AF: 0.397 AC: 6037 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1403 AN: 3466

East Asian (EAS) AF: 0.0431 AC: 223 AN: 5180

South Asian (SAS) AF: 0.262 AC: 1257 AN: 4798

European-Finnish (FIN) AF: 0.327 AC: 3435 AN: 10494

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27132 AN: 67906

Other (OTH) AF: 0.428 AC: 902 AN: 2106

Alfa AF: 0.406 Hom.: 12713

Bravo AF: 0.472

Asia WGS AF: 0.184 AC: 645 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.23
DANN	Benign	0.18
PhyloP100		-0.74
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: rs10948238; hg19: chr6-45511541;