6-45422996-G-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 257096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-45422996-G-C is described in Lovd as [Benign].
• 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

GnomAD3 exomes AF: 0.102 AC: 21368 AN: 210156 Hom.: 1345 AF XY: 0.108 AC XY: 12660 AN XY: 116994

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 SAS exome AF: 0.182

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

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.0693

Gnomad4 ASJ exome AF: 0.0450

Gnomad4 EAS exome AF: 0.0763

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.173

Gnomad4 NFE exome AF: 0.0976

Gnomad4 OTH exome AF: 0.0903

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

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0829

Gnomad4 ASJ AF: 0.0513

Gnomad4 EAS AF: 0.0546

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.0978

Gnomad4 OTH AF: 0.0697

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

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: rs3749864; hg19: chr6-45390733;