chr16-28933075-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.146

Publications

63 publications found

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]

CD19 links:

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]

RABEP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 318803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
CD19	NM_001770.6 link	c.520C>G	p.Leu174Val	missense_variant	Exon 3 of 15	ENST00000538922.8	NP_001761.3	P15391-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD19	ENST00000538922.8 link	c.520C>G	p.Leu174Val	missense_variant	Exon 3 of 15	5	NM_001770.6	ENSP00000437940.2		P15391-1

Frequencies

GnomAD3 genomes

AF:

0.763

AC:

116003

AN:

151938

Hom.:

45534

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.719

AC:

179615

AN:

249700

AF XY:

0.725

show subpopulations

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 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.:

AF XY:

0.701

AC XY:

509168

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.954

AC:

31946

AN:

33480

American (AMR)

AF:

0.548

AC:

24493

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.766

AC:

20023

AN:

26134

East Asian (EAS)

AF:

0.908

AC:

36047

AN:

39692

South Asian (SAS)

AF:

0.822

AC:

70879

AN:

86252

European-Finnish (FIN)

AF:

0.683

AC:

36018

AN:

52768

Middle Eastern (MID)

AF:

0.834

AC:

4808

AN:

5768

European-Non Finnish (NFE)

AF:

0.675

AC:

750183

AN:

1111696

Other (OTH)

AF:

0.726

AC:

43834

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

16574

33149

49723

66298

82872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19440

38880

58320

77760

97200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.764

AC:

116100

AN:

152056

Hom.:

45584

Cov.:

AF XY:

0.765

AC XY:

56836

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.940

AC:

38977

AN:

41486

American (AMR)

AF:

0.649

AC:

9908

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.769

AC:

2669

AN:

3472

East Asian (EAS)

AF:

0.904

AC:

4660

AN:

5154

South Asian (SAS)

AF:

0.832

AC:

3997

AN:

4806

European-Finnish (FIN)

AF:

0.688

AC:

7287

AN:

10598

Middle Eastern (MID)

AF:

0.823

AC:

242

AN:

294

European-Non Finnish (NFE)

AF:

0.677

AC:

45999

AN:

67942

Other (OTH)

AF:

0.770

AC:

1628

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1306

2613

3919

5226

6532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

848

1696

2544

3392

4240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 3

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.4

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.31

.;T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.13

T;T;.

MetaRNN

Benign

7.5e-7

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

N;N;N

PhyloP100

0.15

PrimateAI

Benign

0.27

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

GERP RS

2.8

Varity_R

0.13

gMVP

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over