chr6-45533815-A-G

Variant names:

• chr6-45533815-A-G
• rs7748231
• NM_001024630.4:c.1022-11402A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001024630.4(RUNX2):​c.1022-11402A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 151,374 control chromosomes in the GnomAD database, including 17,639 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 (17639 hom., cov: 29)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.329
• Publications: 7 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 = 0.638 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.1022-11402A>G		intron_variant	Intron 7 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.980-11402A>G		intron_variant	Intron 5 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.1022-13012A>G		intron_variant	Intron 7 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.980-13012A>G		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.1022-11402A>G		intron_variant	Intron 7 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70286 AN: 151268 Hom.: 17604 Cov.: 29

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.447

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.381

Gnomad NFE AF: 0.433

Gnomad OTH AF: 0.436

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

GnomAD4 genome AF: 0.465 AC: 70365 AN: 151374 Hom.: 17639 Cov.: 29 AF XY: 0.455 AC XY: 33620 AN XY: 73906

African (AFR) AF: 0.645 AC: 26519 AN: 41142

American (AMR) AF: 0.408 AC: 6213 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 1546 AN: 3462

East Asian (EAS) AF: 0.0432 AC: 223 AN: 5162

South Asian (SAS) AF: 0.275 AC: 1315 AN: 4780

European-Finnish (FIN) AF: 0.369 AC: 3842 AN: 10406

Middle Eastern (MID) AF: 0.395 AC: 113 AN: 286

European-Non Finnish (NFE) AF: 0.433 AC: 29375 AN: 67912

Other (OTH) AF: 0.432 AC: 905 AN: 2096

Alfa AF: 0.436 Hom.: 63804

Bravo AF: 0.475

Asia WGS AF: 0.187 AC: 654 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	0.43
DANN	Benign	0.25
PhyloP100		-0.33
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: rs7748231; hg19: chr6-45501552;