chr6-45421552-T-C

Variant names:

• chr6-45421552-T-C
• rs7771980
• NM_001024630.4:c.59-1041T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 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

ENSG00000271857 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-1041T>C		intron_variant	Intron 2 of 8	ENST00000647337.2	NP_001019801.3
LOC124901324	XR_007059602.1	n.480A>G		non_coding_transcript_exon_variant	Exon 2 of 2
RUNX2	NM_001015051.4	c.59-1041T>C		intron_variant	Intron 2 of 7		NP_001015051.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-1041T>C		intron_variant	Intron 2 of 8		NM_001024630.4	ENSP00000495497.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 2 AN: 12

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.0226 AC: 938 AN: 41562

American (AMR) AF: 0.0832 AC: 1273 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3472

East Asian (EAS) AF: 0.0555 AC: 287 AN: 5172

South Asian (SAS) AF: 0.181 AC: 873 AN: 4812

European-Finnish (FIN) AF: 0.188 AC: 1994 AN: 10588

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0980 AC: 6668 AN: 68010

Other (OTH) AF: 0.0710 AC: 150 AN: 2112

Alfa AF: 0.0876 Hom.: 755

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

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Benign	0.85
PhyloP100		0.061
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: rs7771980; hg19: chr6-45389289;