rs2904880

chr16-28933075-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001770.6(CD19):c.520C>G(p.Leu174Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.703 in 1,612,920 control chromosomes in the GnomAD database, including 404,691 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L174L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.76 (45584 hom., cov: 31)
  • Exomes 𝑓: 0.70 (359107 hom.)
• Consequence: CD19 NM_001770.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.146

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]

RABEP2 (HGNC:24817): (rabaptin, RAB GTPase binding effector protein 2) Predicted to enable GTPase activator activity and growth factor activity. Involved in regulation of cilium assembly. Located in cytosol; intracellular membrane-bounded organelle; and microtubule organizing center. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.5003027E-7).
• BP6: Variant 16-28933075-C-G is Benign according to our data. Variant chr16-28933075-C-G is described in ClinVar as [Benign]. Clinvar id is 318803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28933075-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CD19	NM_001770.6	c.520C>G	p.Leu174Val	missense_variant	3/15	ENST00000538922.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CD19	ENST00000538922.8	c.520C>G	p.Leu174Val	missense_variant	3/15	5	NM_001770.6	P3

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116003 AN: 151938 Hom.: 45534 Cov.: 31

Gnomad AFR AF: 0.939

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.650

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.904

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.772

GnomAD3 exomes AF: 0.719 AC: 179615 AN: 249700 Hom.: 66460 AF XY: 0.725 AC XY: 97949 AN XY: 135020

Gnomad AFR exome AF: 0.944

Gnomad AMR exome AF: 0.546

Gnomad ASJ exome AF: 0.762

Gnomad EAS exome AF: 0.916

Gnomad SAS exome AF: 0.823

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.682

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.697 AC: 1018231 AN: 1460864 Hom.: 359107 Cov.: 55 AF XY: 0.701 AC XY: 509168 AN XY: 726728

Gnomad4 AFR exome AF: 0.954

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.766

Gnomad4 EAS exome AF: 0.908

Gnomad4 SAS exome AF: 0.822

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.675

Gnomad4 OTH exome AF: 0.726

GnomAD4 genome AF: 0.764 AC: 116100 AN: 152056 Hom.: 45584 Cov.: 31 AF XY: 0.765 AC XY: 56836 AN XY: 74328

Gnomad4 AFR AF: 0.940

Gnomad4 AMR AF: 0.649

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.904

Gnomad4 SAS AF: 0.832

Gnomad4 FIN AF: 0.688

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.770

Alfa AF: 0.708 Hom.: 11025

Bravo AF: 0.767

TwinsUK AF: 0.670 AC: 2485

ALSPAC AF: 0.666 AC: 2567

ESP6500AA AF: 0.929 AC: 4084

ESP6500EA AF: 0.688 AC: 5913

ExAC AF: 0.729 AC: 88442

Asia WGS AF: 0.812 AC: 2827 AN: 3478

EpiCase AF: 0.703

EpiControl AF: 0.705

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 3 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 86% of patients studied by a panel of primary immunodeficiencies. Number of patients: 82. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	1.4
Dann	Benign	0.82
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.13	T;T;.
MetaRNN	Benign	7.5e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.072
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.024
MPC		0.25
ClinPred		0.0067	T
GERP RS		2.8
Varity_R		0.13
gMVP		0.22

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: rs2904880; hg19: chr16-28944396; COSMIC: COSV61188398; COSMIC: COSV61188398;