rs2227939

Variant names:

• chr22-23289614-T-C
• rs2227939
• NM_004327.4:c.2700T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004327.4(BCR):​c.2700T>C​(p.Asn900Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,612,806 control chromosomes in the GnomAD database, including 72,629 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 0.34 (10118 hom., cov: 34)
  • Exomes 𝑓: 0.28 (62511 hom.)
• Consequence: BCR NM_004327.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579
• Publications: 18 publications found

Genes affected

BCR (HGNC:1014): (BCR activator of RhoGEF and GTPase) A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein which is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint. Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The unregulated tyrosine kinase activity of BCR-ABL1 contributes to the immortality of leukaemic cells. The BCR protein has serine/threonine kinase activity and is a GTPase-activating protein for p21rac and other kinases. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2020]

ENSG00000296232 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=0.579 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004327.4. 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
	BCR	NM_004327.4	MANE Select	c.2700T>C	p.Asn900Asn	synonymous	Exon 13 of 23	NP_004318.3
	BCR	NM_021574.3		c.2700T>C	p.Asn900Asn	synonymous	Exon 13 of 22	NP_067585.2	P11274-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCR	ENST00000305877.13	TSL:1 MANE Select	c.2700T>C	p.Asn900Asn	synonymous	Exon 13 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.2700T>C	p.Asn900Asn	synonymous	Exon 13 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.2721T>C	p.Asn907Asn	synonymous	Exon 13 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52240 AN: 152022 Hom.: 10101 Cov.: 34

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.344

GnomAD2 exomes AF: 0.286 AC: 71806 AN: 250794 AF XY: 0.286

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.0577

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.284 AC: 415462 AN: 1460666 Hom.: 62511 Cov.: 34 AF XY: 0.286 AC XY: 207730 AN XY: 726666

African (AFR) AF: 0.538 AC: 17980 AN: 33446

American (AMR) AF: 0.303 AC: 13524 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.378 AC: 9871 AN: 26126

East Asian (EAS) AF: 0.0610 AC: 2423 AN: 39690

South Asian (SAS) AF: 0.306 AC: 26409 AN: 86194

European-Finnish (FIN) AF: 0.196 AC: 10457 AN: 53412

Middle Eastern (MID) AF: 0.440 AC: 2536 AN: 5768

European-Non Finnish (NFE) AF: 0.283 AC: 314321 AN: 1111020

Other (OTH) AF: 0.297 AC: 17941 AN: 60350

GnomAD4 genome AF: 0.344 AC: 52304 AN: 152140 Hom.: 10118 Cov.: 34 AF XY: 0.336 AC XY: 24999 AN XY: 74396

African (AFR) AF: 0.517 AC: 21447 AN: 41460

American (AMR) AF: 0.326 AC: 4989 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1300 AN: 3472

East Asian (EAS) AF: 0.0604 AC: 313 AN: 5182

South Asian (SAS) AF: 0.286 AC: 1379 AN: 4824

European-Finnish (FIN) AF: 0.189 AC: 2007 AN: 10608

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19789 AN: 67978

Other (OTH) AF: 0.341 AC: 721 AN: 2114

Alfa AF: 0.323 Hom.: 7084

Bravo AF: 0.362

Asia WGS AF: 0.189 AC: 661 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.318

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.8
DANN	Benign	0.60
PhyloP100		0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs2227939; hg19: chr22-23631801; COSMIC: COSV59932322; COSMIC: COSV59932322;