6-45422996-G-C

Variant names:

• chr6-45422996-G-C
• rs3749864
• NM_001024630.4:c.423+39G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001024630.4(RUNX2):​c.423+39G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 1,591,676 control chromosomes in the GnomAD database, including 8,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (714 hom., cov: 31)
  • Exomes 𝑓: 0.10 (8142 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.45
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 6-45422996-G-C is Benign according to our data. Variant chr6-45422996-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.423+39G>C		intron_variant	Intron 3 of 8	ENST00000647337.2	NP_001019801.3
RUNX2	NM_001369405.1	c.381+39G>C		intron_variant	Intron 1 of 6		NP_001356334.1
RUNX2	NM_001015051.4	c.423+39G>C		intron_variant	Intron 3 of 7		NP_001015051.3
RUNX2	NM_001278478.2	c.381+39G>C		intron_variant	Intron 1 of 5		NP_001265407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.423+39G>C		intron_variant	Intron 3 of 8		NM_001024630.4	ENSP00000495497.1

Frequencies

GnomAD3 genomes AF: 0.0800 AC: 12138 AN: 151802 Hom.: 717 Cov.: 31

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.0513

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0978

Gnomad OTH AF: 0.0699

GnomAD2 exomes AF: 0.102 AC: 21368 AN: 210156 AF XY: 0.108

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0690

Gnomad ASJ exome AF: 0.0420

Gnomad EAS exome AF: 0.0526

Gnomad FIN exome AF: 0.176

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0900

GnomAD4 exome AF: 0.101 AC: 144890 AN: 1439756 Hom.: 8142 Cov.: 35 AF XY: 0.104 AC XY: 74149 AN XY: 715940

African (AFR) AF: 0.0138 AC: 455 AN: 32984

American (AMR) AF: 0.0693 AC: 3014 AN: 43520

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 1157 AN: 25704

East Asian (EAS) AF: 0.0763 AC: 2961 AN: 38800

South Asian (SAS) AF: 0.186 AC: 15813 AN: 84968

European-Finnish (FIN) AF: 0.173 AC: 7959 AN: 45920

Middle Eastern (MID) AF: 0.0946 AC: 393 AN: 4156

European-Non Finnish (NFE) AF: 0.0976 AC: 107770 AN: 1104280

Other (OTH) AF: 0.0903 AC: 5368 AN: 59424

GnomAD4 genome AF: 0.0799 AC: 12136 AN: 151920 Hom.: 714 Cov.: 31 AF XY: 0.0858 AC XY: 6369 AN XY: 74218

African (AFR) AF: 0.0166 AC: 690 AN: 41482

American (AMR) AF: 0.0829 AC: 1268 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0513 AC: 178 AN: 3470

East Asian (EAS) AF: 0.0546 AC: 278 AN: 5088

South Asian (SAS) AF: 0.183 AC: 878 AN: 4808

European-Finnish (FIN) AF: 0.189 AC: 1996 AN: 10576

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.0978 AC: 6638 AN: 67890

Other (OTH) AF: 0.0697 AC: 147 AN: 2110

Alfa AF: 0.0539 Hom.: 67

Bravo AF: 0.0669

Asia WGS AF: 0.105 AC: 365 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cleidocranial dysostosis;C3549874:Metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome Benign:1

Oct 13, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 20, 2018

GeneDx

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	-0.68
CADD	Benign	8.0
DANN	Benign	0.89
PhyloP100		-1.4
PromoterAI		-0.058	Neutral
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: rs3749864; hg19: chr6-45390733;