rs34763945

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.1541G>A(p.Arg514His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0566 in 1,613,794 control chromosomes in the GnomAD database, including 3,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R514C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.040 ( 174 hom., cov: 31)

Exomes 𝑓: 0.058 ( 2895 hom. )

Consequence

CD19
NM_001770.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.445

Publications

17 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 Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CD19 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=0.0027741194).

BP6

Variant 16-28938730-G-A is Benign according to our data. Variant chr16-28938730-G-A is described in ClinVar as [Benign]. Clinvar id is 318811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD19	NM_001770.6 link	c.1541G>A	p.Arg514His	missense_variant	Exon 13 of 15	ENST00000538922.8	NP_001761.3	P15391-1
CD19	NM_001178098.2 link	c.1544G>A	p.Arg515His	missense_variant	Exon 13 of 15		NP_001171569.1	P15391-2
CD19	NM_001385732.1 link	c.1274G>A	p.Arg425His	missense_variant	Exon 12 of 14		NP_001372661.1
CD19	NR_169755.1 link	n.1883G>A		non_coding_transcript_exon_variant	Exon 12 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CD19	ENST00000538922.8 link	c.1541G>A	p.Arg514His	missense_variant	Exon 13 of 15	5	NM_001770.6	ENSP00000437940.2	P15391-1
CD19	ENST00000324662.8 link	c.1544G>A	p.Arg515His	missense_variant	Exon 13 of 15	1		ENSP00000313419.4	P15391-2
CD19	ENST00000565089.5 link	n.1975G>A		non_coding_transcript_exon_variant	Exon 11 of 13	2
CD19	ENST00000567368.1 link	n.624G>A		non_coding_transcript_exon_variant	Exon 5 of 7	3

Frequencies

GnomAD3 genomes

AF:

0.0402

AC:

6118

AN:

152092

Hom.:

174

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0272

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0212

Gnomad FIN

AF:

0.0687

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0626

Gnomad OTH

AF:

0.0392

GnomAD2 exomes

AF:

0.0399

AC:

10037

AN:

251404

AF XY:

0.0414

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.0208

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0643

Gnomad NFE exome

AF:

0.0585

Gnomad OTH exome

AF:

0.0426

GnomAD4 exome

AF:

0.0583

AC:

85189

AN:

1461584

Hom.:

2895

Cov.:

AF XY:

0.0571

AC XY:

41519

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.00914

AC:

306

AN:

33480

American (AMR)

AF:

0.0204

AC:

913

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0199

AC:

519

AN:

26136

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.0229

AC:

1977

AN:

86256

European-Finnish (FIN)

AF:

0.0635

AC:

3393

AN:

53398

Middle Eastern (MID)

AF:

0.0198

AC:

114

AN:

5766

European-Non Finnish (NFE)

AF:

0.0672

AC:

74666

AN:

1111734

Other (OTH)

AF:

0.0546

AC:

3297

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

4297

8595

12892

17190

21487

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0402

AC:

6123

AN:

152210

Hom.:

174

Cov.:

AF XY:

0.0393

AC XY:

2922

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0105

AC:

437

AN:

41560

American (AMR)

AF:

0.0271

AC:

414

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4818

European-Finnish (FIN)

AF:

0.0687

AC:

727

AN:

10584

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0626

AC:

4260

AN:

68008

Other (OTH)

AF:

0.0388

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

299

598

897

1196

1495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0514

Hom.:

503

Bravo

AF:

0.0366

TwinsUK

AF:

0.0712

AC:

264

ALSPAC

AF:

0.0646

AC:

249

ESP6500AA

AF:

0.0141

AC:

ESP6500EA

AF:

0.0643

AC:

553

ExAC

AF:

0.0398

AC:

4827

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0612

EpiControl

AF:

0.0577

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 09, 2021

GeneDx

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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Immunodeficiency, common variable, 3

Benign:2

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 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

.;D;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.68

T;T;.

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L;.

PhyloP100

0.45

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Benign

0.019

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.088

T;T;T

Polyphen

0.20

.;B;.

Vest4

0.070

MPC

0.31

ClinPred

0.025

GERP RS

0.66

Varity_R

0.051

Mutation Taster

=99/1

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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rs34763945

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