rs886037921

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

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

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.209
Variant links:
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]

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ACMG classification

Classification made for transcript

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
CD19NM_001770.6 linkuse as main transcriptc.1464del p.Ser489AlafsTer15 frameshift_variant 12/15 ENST00000538922.8
CD19NM_001178098.2 linkuse as main transcriptc.1464del p.Ser489AlafsTer16 frameshift_variant 12/15
CD19NM_001385732.1 linkuse as main transcriptc.1197del p.Ser400AlafsTer15 frameshift_variant 11/14
CD19NR_169755.1 linkuse as main transcriptn.1806del non_coding_transcript_exon_variant 11/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CD19ENST00000538922.8 linkuse as main transcriptc.1464del p.Ser489AlafsTer15 frameshift_variant 12/155 NM_001770.6 P3P15391-1
CD19ENST00000324662.8 linkuse as main transcriptc.1464del p.Ser489AlafsTer16 frameshift_variant 12/151 A2P15391-2
CD19ENST00000565089.5 linkuse as main transcriptn.1898del non_coding_transcript_exon_variant 10/132
CD19ENST00000567368.1 linkuse as main transcriptn.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
LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 3 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 13, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs886037921; hg19: chr16-28949120; API