chr6-45422351-G-T

Position:

• chr6-45422351-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001024630.4(RUNX2):​c.59-242G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 500,894 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 30)
  • Exomes 𝑓: 0.014 (46 hom.)
• Consequence: RUNX2 NM_001024630.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.12

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=-0.71).
• BP6: Variant 6-45422351-G-T is Benign according to our data. Variant chr6-45422351-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1196572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.012 (1820/151824) while in subpopulation NFE AF= 0.0185 (1255/67902). AF 95% confidence interval is 0.0176. There are 20 homozygotes in gnomad4. There are 861 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1820 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RUNX2	NM_001024630.4	c.59-242G>T		intron_variant		ENST00000647337.2	NP_001019801.3
RUNX2	NM_001278478.2	c.-226G>T		5_prime_UTR_variant	1/6		NP_001265407.1
RUNX2	NM_001369405.1	c.-226G>T		5_prime_UTR_variant	1/7		NP_001356334.1
RUNX2	NM_001015051.4	c.59-242G>T		intron_variant			NP_001015051.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RUNX2	ENST00000647337.2	c.59-242G>T		intron_variant			NM_001024630.4	ENSP00000495497	P4

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1818 AN: 151710 Hom.: 20 Cov.: 30

Gnomad AFR AF: 0.00334

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.00918

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.0139 AC: 4842 AN: 349070 Hom.: 46 Cov.: 0 AF XY: 0.0138 AC XY: 2545 AN XY: 184734

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.00698

Gnomad4 ASJ exome AF: 0.00632

Gnomad4 EAS exome AF: 0.000104

Gnomad4 SAS exome AF: 0.0103

Gnomad4 FIN exome AF: 0.00909

Gnomad4 NFE exome AF: 0.0173

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0120 AC: 1820 AN: 151824 Hom.: 20 Cov.: 30 AF XY: 0.0116 AC XY: 861 AN XY: 74198

Gnomad4 AFR AF: 0.00333

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.00918

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0137 Hom.: 1

Bravo AF: 0.0116

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.90

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: rs146028707; hg19: chr6-45390088;