rs2772395

Variant names:

• chr6-45553712-G-A
• rs2772395
• ENST00000576263.5:c.1021+41305G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-45553712-G-A
• chr6-45553712-G-T

Variant summary

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

The ENST00000576263.5(RUNX2):​c.1021+41305G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.353 in 151,978 control chromosomes in the GnomAD database, including 9,782 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 0.35 (9782 hom., cov: 32)
• Consequence: RUNX2 ENST00000576263.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.328
• 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000576263.5	c.1021+41305G>A		intron_variant	Intron 6 of 6	5		ENSP00000458178.1
RUNX2	ENST00000478660.6	n.*178+40059G>A		intron_variant	Intron 5 of 5	5		ENSP00000460188.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53662 AN: 151858 Hom.: 9788 Cov.: 32

Gnomad AFR AF: 0.266

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.381

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.404

Gnomad OTH AF: 0.354

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

GnomAD4 genome AF: 0.353 AC: 53662 AN: 151978 Hom.: 9782 Cov.: 32 AF XY: 0.353 AC XY: 26248 AN XY: 74258

African (AFR) AF: 0.265 AC: 10996 AN: 41444

American (AMR) AF: 0.366 AC: 5594 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 1322 AN: 3466

East Asian (EAS) AF: 0.268 AC: 1382 AN: 5166

South Asian (SAS) AF: 0.323 AC: 1555 AN: 4816

European-Finnish (FIN) AF: 0.408 AC: 4297 AN: 10540

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.404 AC: 27434 AN: 67954

Other (OTH) AF: 0.351 AC: 742 AN: 2116

Alfa AF: 0.384 Hom.: 21675

Bravo AF: 0.346

Asia WGS AF: 0.247 AC: 860 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.17
DANN	Benign	0.71
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2772395; hg19: chr6-45521449;