22-23181566-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004327.4(BCR):c.606C>T(p.Ser202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,612,976 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (9 hom.)
• Consequence: BCR NM_004327.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.617

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 22-23181566-C-T is Benign according to our data. Variant chr22-23181566-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 780633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.617 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00614 (936/152352) while in subpopulation AFR AF= 0.0204 (850/41586). AF 95% confidence interval is 0.0193. There are 8 homozygotes in gnomad4. There are 415 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 935 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCR	NM_004327.4	c.606C>T	p.Ser202=	synonymous_variant	1/23	ENST00000305877.13
BCR	NM_021574.3	c.606C>T	p.Ser202=	synonymous_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCR	ENST00000305877.13	c.606C>T	p.Ser202=	synonymous_variant	1/23	1	NM_004327.4	P1
BCR	ENST00000359540.7	c.606C>T	p.Ser202=	synonymous_variant	1/22	1
BCR	ENST00000479188.5	n.129+1734C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00614 AC: 935 AN: 152234 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00171 AC: 419 AN: 245714 Hom.: 6 AF XY: 0.00120 AC XY: 161 AN XY: 134166

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.000683 AC: 997 AN: 1460624 Hom.: 9 Cov.: 33 AF XY: 0.000629 AC XY: 457 AN XY: 726644

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.00146

GnomAD4 genome AF: 0.00614 AC: 936 AN: 152352 Hom.: 8 Cov.: 33 AF XY: 0.00557 AC XY: 415 AN XY: 74502

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.00333

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00314 Hom.: 4

Bravo AF: 0.00699

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2018

- -

Acute lymphoid leukemia;C0279543:Chronic myelogenous leukemia, BCR-ABL1 positive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	5.3
Dann	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs147507158; hg19: chr22-23523753; COSMIC: COSV59933390; COSMIC: COSV59933390;