rs2249650

Variant names:

• chr21-34808689-A-G
• rs2249650
• NM_001754.5:c.806-9227T>C

Your query was ambiguous. Multiple possible variants found:

• chr21-34808689-A-G
• chr21-34808689-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001754.5(RUNX1):​c.806-9227T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,996 control chromosomes in the GnomAD database, including 20,069 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (20069 hom., cov: 32)
• Consequence: RUNX1 NM_001754.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.88
• Publications: 13 publications found

Genes affected

RUNX1 (HGNC:10471): (RUNX family transcription factor 1) Core binding factor (CBF) is a heterodimeric transcription factor that binds to the core element of many enhancers and promoters. The protein encoded by this gene represents the alpha subunit of CBF and is thought to be involved in the development of normal hematopoiesis. Chromosomal translocations involving this gene are well-documented and have been associated with several types of leukemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RUNX1 Gene-Disease associations (from GenCC):

• hereditary thrombocytopenia and hematologic cancer predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, G2P
• acute myeloid leukemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001754.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	NM_001754.5	MANE Select	c.806-9227T>C		intron	N/A	NP_001745.2
	RUNX1	NM_001001890.3		c.725-9227T>C		intron	N/A	NP_001001890.1	Q01196-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RUNX1	ENST00000675419.1	MANE Select	c.806-9227T>C		intron	N/A	ENSP00000501943.1	Q01196-8
	RUNX1	ENST00000300305.7	TSL:1	c.806-9227T>C		intron	N/A	ENSP00000300305.3	Q01196-8
	RUNX1	ENST00000344691.8	TSL:1	c.725-9227T>C		intron	N/A	ENSP00000340690.4	Q01196-1

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77691 AN: 151878 Hom.: 20040 Cov.: 32

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.541

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.468

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.517

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 77768 AN: 151996 Hom.: 20069 Cov.: 32 AF XY: 0.508 AC XY: 37706 AN XY: 74290

African (AFR) AF: 0.522 AC: 21613 AN: 41442

American (AMR) AF: 0.514 AC: 7850 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1840 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1969 AN: 5154

South Asian (SAS) AF: 0.467 AC: 2249 AN: 4812

European-Finnish (FIN) AF: 0.463 AC: 4895 AN: 10568

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35617 AN: 67970

Other (OTH) AF: 0.518 AC: 1096 AN: 2114

Alfa AF: 0.527 Hom.: 38351

Bravo AF: 0.517

Asia WGS AF: 0.453 AC: 1576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.73
PhyloP100		1.9

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: rs2249650; hg19: chr21-36180986; COSMIC: COSV55874886;