22-23181192-C-A

Variant names:

• chr22-23181192-C-A
• rs761816882
• NM_004327.4:c.232C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_004327.4(BCR):​c.232C>A​(p.Arg78Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000341 in 1,173,180 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BCR NM_004327.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.719
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP7: Synonymous conserved (PhyloP=0.719 with no splicing effect.

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.232C>A	p.Arg78Arg	synonymous	Exon 1 of 23	NP_004318.3
	BCR	NM_021574.3		c.232C>A	p.Arg78Arg	synonymous	Exon 1 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.232C>A	p.Arg78Arg	synonymous	Exon 1 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.232C>A	p.Arg78Arg	synonymous	Exon 1 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.232C>A	p.Arg78Arg	synonymous	Exon 1 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000341 AC: 4 AN: 1173180 Hom.: 0 Cov.: 30 AF XY: 0.00000526 AC XY: 3 AN XY: 570792

African (AFR) AF: 0.00 AC: 0 AN: 24590

American (AMR) AF: 0.00 AC: 0 AN: 21518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18310

East Asian (EAS) AF: 0.00 AC: 0 AN: 25028

South Asian (SAS) AF: 0.00 AC: 0 AN: 46896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4776

European-Non Finnish (NFE) AF: 0.00000422 AC: 4 AN: 947492

Other (OTH) AF: 0.00 AC: 0 AN: 45320

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.95
PhyloP100		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		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: rs761816882; hg19: chr22-23523379;