22-23199301-C-T

Variant names:

• chr22-23199301-C-T
• rs2071436
• ENST00000487679.1:n.145C>T

Variant summary

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

The ENST00000487679.1(BCR):​n.145C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 517,964 control chromosomes in the GnomAD database, including 17,697 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 0.23 (4450 hom., cov: 31)
  • Exomes 𝑓: 0.26 (13247 hom.)
• Consequence: BCR ENST00000487679.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 20 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (REVEL=0.045).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCR	NM_004327.4	c.1279+17062C>T		intron_variant	Intron 1 of 22	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.1279+17062C>T		intron_variant	Intron 1 of 21		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.1279+17062C>T		intron_variant	Intron 1 of 22	1	NM_004327.4	ENSP00000303507.8

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34588 AN: 151902 Hom.: 4450 Cov.: 31

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.308

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.225

GnomAD2 exomes AF: 0.266 AC: 60795 AN: 228678 AF XY: 0.261

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.358

Gnomad FIN exome AF: 0.289

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.261 AC: 95382 AN: 365942 Hom.: 13247 Cov.: 0 AF XY: 0.253 AC XY: 53112 AN XY: 209892

African (AFR) AF: 0.115 AC: 1208 AN: 10488

American (AMR) AF: 0.356 AC: 12874 AN: 36140

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 2818 AN: 11716

East Asian (EAS) AF: 0.366 AC: 4813 AN: 13134

South Asian (SAS) AF: 0.194 AC: 12905 AN: 66668

European-Finnish (FIN) AF: 0.293 AC: 4943 AN: 16888

Middle Eastern (MID) AF: 0.275 AC: 782 AN: 2846

European-Non Finnish (NFE) AF: 0.266 AC: 50885 AN: 191490

Other (OTH) AF: 0.251 AC: 4154 AN: 16572

GnomAD4 genome AF: 0.228 AC: 34596 AN: 152022 Hom.: 4450 Cov.: 31 AF XY: 0.230 AC XY: 17102 AN XY: 74292

African (AFR) AF: 0.114 AC: 4739 AN: 41490

American (AMR) AF: 0.308 AC: 4705 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 833 AN: 3470

East Asian (EAS) AF: 0.351 AC: 1810 AN: 5156

South Asian (SAS) AF: 0.202 AC: 975 AN: 4820

European-Finnish (FIN) AF: 0.296 AC: 3129 AN: 10556

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17731 AN: 67950

Other (OTH) AF: 0.222 AC: 469 AN: 2110

Alfa AF: 0.254 Hom.: 4793

Bravo AF: 0.226

Asia WGS AF: 0.275 AC: 955 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.76
PhyloP100		-2.0
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: rs2071436; hg19: chr22-23541488; COSMIC: COSV59927241;