rs7771980

Positions:

• chr6-45421552-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001024630.4(RUNX2):​c.59-1041T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0816 in 152,242 control chromosomes in the GnomAD database, including 720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.082 (720 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0610

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 6-45421552-T-C is Benign according to our data. Variant chr6-45421552-T-C is described in ClinVar as [Benign]. Clinvar id is 1164339.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUNX2	NM_001024630.4	c.59-1041T>C		intron_variant		ENST00000647337.2
LOC124901324	XR_007059602.1	n.480A>G		non_coding_transcript_exon_variant	2/2
RUNX2	NM_001015051.4	c.59-1041T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-1041T>C		intron_variant			NM_001024630.4	P4
	ENST00000606796.1	n.454A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0817 AC: 12426 AN: 152108 Hom.: 723 Cov.: 32

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0834

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0980

Gnomad OTH AF: 0.0713

GnomAD4 exome AF: 0.125 AC: 2 AN: 16 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 2 AN XY: 12

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.167

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0816 AC: 12424 AN: 152226 Hom.: 720 Cov.: 32 AF XY: 0.0874 AC XY: 6506 AN XY: 74426

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.0832

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.0555

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.0980

Gnomad4 OTH AF: 0.0710

Alfa AF: 0.0904 Hom.: 604

Bravo AF: 0.0690

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs7771980; hg19: chr6-45389289;