6-45464528-C-T

Variant names:

• chr6-45464528-C-T
• rs2790103
• NM_001024630.4:c.685+26477C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001024630.4(RUNX2):​c.685+26477C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 152,016 control chromosomes in the GnomAD database, including 6,221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency: Genomes: 𝑓 0.27 (6221 hom., cov: 32)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.415
• Publications: 6 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-45464528-C-T is Benign according to our data. Variant chr6-45464528-C-T is described in ClinVar as Benign. ClinVar VariationId is 3345352.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024630.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	NM_001024630.4	MANE Select	c.685+26477C>T		intron	N/A	NP_001019801.3
	RUNX2	NM_001369405.1		c.643+26477C>T		intron	N/A	NP_001356334.1
	RUNX2	NM_001015051.4		c.685+26477C>T		intron	N/A	NP_001015051.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX2	ENST00000647337.2	MANE Select	c.685+26477C>T		intron	N/A	ENSP00000495497.1
	RUNX2	ENST00000359524.7	TSL:1	c.643+26477C>T		intron	N/A	ENSP00000352514.5
	RUNX2	ENST00000625924.1	TSL:1	c.643+26477C>T		intron	N/A	ENSP00000485863.1

Frequencies

GnomAD3 genomes AF: 0.273 AC: 41536 AN: 151898 Hom.: 6221 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.289

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.0462

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.269

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

GnomAD4 genome AF: 0.273 AC: 41532 AN: 152016 Hom.: 6221 Cov.: 32 AF XY: 0.271 AC XY: 20155 AN XY: 74316

African (AFR) AF: 0.170 AC: 7031 AN: 41458

American (AMR) AF: 0.288 AC: 4406 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1370 AN: 3466

East Asian (EAS) AF: 0.0458 AC: 237 AN: 5178

South Asian (SAS) AF: 0.268 AC: 1290 AN: 4812

European-Finnish (FIN) AF: 0.311 AC: 3281 AN: 10550

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.340 AC: 23126 AN: 67956

Other (OTH) AF: 0.267 AC: 562 AN: 2108

Alfa AF: 0.200 Hom.: 536

Bravo AF: 0.266

Asia WGS AF: 0.157 AC: 550 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

RUNX2-related disorder Benign:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.65
PhyloP100		0.41
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: rs2790103; hg19: chr6-45432265;