16-28937799-AC-A

Position:

• chr16-28937799-AC-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001770.6(CD19):​c.1464del​(p.Ser489AlafsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CD19 NM_001770.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.209

Genes affected

CD19 (HGNC:1633): (CD19 molecule) This gene encodes a member of the immunoglobulin gene superfamily. Expression of this cell surface protein is restricted to B cell lymphocytes. This protein is a reliable marker for pre-B cells but its expression diminishes during terminal B cell differentiation in antibody secreting plasma cells. The protein has two N-terminal extracellular Ig-like domains separated by a non-Ig-like domain, a hydrophobic transmembrane domain, and a large C-terminal cytoplasmic domain. This protein forms a complex with several membrane proteins including complement receptor type 2 (CD21) and tetraspanin (CD81) and this complex reduces the threshold for antigen-initiated B cell activation. Activation of this B-cell antigen receptor complex activates the phosphatidylinositol 3-kinase signalling pathway and the subsequent release of intracellular stores of calcium ions. This protein is a target of chimeric antigen receptor (CAR) T-cells used in the treatment of lymphoblastic leukemia. Mutations in this gene are associated with the disease common variable immunodeficiency 3 (CVID3) which results in a failure of B-cell differentiation and impaired secretion of immunoglobulins. CVID3 is characterized by hypogammaglobulinemia, an inability to mount an antibody response to antigen, and recurrent bacterial infections. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-28937799-AC-A is Pathogenic according to our data. Variant chr16-28937799-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 254196.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD19	NM_001770.6	c.1464del	p.Ser489AlafsTer15	frameshift_variant	12/15	ENST00000538922.8
CD19	NM_001178098.2	c.1464del	p.Ser489AlafsTer16	frameshift_variant	12/15
CD19	NM_001385732.1	c.1197del	p.Ser400AlafsTer15	frameshift_variant	11/14
CD19	NR_169755.1	n.1806del		non_coding_transcript_exon_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD19	ENST00000538922.8	c.1464del	p.Ser489AlafsTer15	frameshift_variant	12/15	5	NM_001770.6	P3
CD19	ENST00000324662.8	c.1464del	p.Ser489AlafsTer16	frameshift_variant	12/15	1		A2
CD19	ENST00000565089.5	n.1898del		non_coding_transcript_exon_variant	10/13	2
CD19	ENST00000567368.1	n.569+123del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency, common variable, 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 13, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs886037921; hg19: chr16-28949120;