16-28933379-G-T

Position:

chr16-28933379-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001770.6(CD19):c.705G>T(p.Pro235Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,826 control chromosomes in the GnomAD database, including 92,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6874 hom., cov: 31)

Exomes 𝑓: 0.33 ( 85644 hom. )

Consequence

CD19
NM_001770.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.29

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:

CD19 (HGNC:):

CD19 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-28933379-G-T is Benign according to our data. Variant chr16-28933379-G-T is described in ClinVar as [Benign]. Clinvar id is 318805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28933379-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.29 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CD19	NM_001770.6 linkuse as main transcript	c.705G>T	p.Pro235Pro	synonymous_variant	4/15	ENST00000538922.8	NP_001761.3	P15391-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CD19	ENST00000538922.8 linkuse as main transcript	c.705G>T	p.Pro235Pro	synonymous_variant	4/15	5	NM_001770.6	ENSP00000437940.2		P15391-1

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41925

AN:

151942

Hom.:

6876

Cov.:

show subpopulations

Gnomad AFR

AF:

0.110

Gnomad AMI

AF:

0.423

Gnomad AMR

AF:

0.279

Gnomad ASJ

AF:

0.409

Gnomad EAS

AF:

0.191

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.442

Gnomad MID

AF:

0.367

Gnomad NFE

AF:

0.357

Gnomad OTH

AF:

0.315

GnomAD3 exomes

AF:

0.298

AC:

74786

AN:

251284

Hom.:

12650

AF XY:

0.297

AC XY:

40399

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.100

Gnomad AMR exome

AF:

0.258

Gnomad ASJ exome

AF:

0.400

Gnomad EAS exome

AF:

0.179

Gnomad SAS exome

AF:

0.136

Gnomad FIN exome

AF:

0.442

Gnomad NFE exome

AF:

0.362

Gnomad OTH exome

AF:

0.341

GnomAD4 exome

AF:

0.334

AC:

488298

AN:

1461766

Hom.:

85644

Cov.:

AF XY:

0.329

AC XY:

239309

AN XY:

727194

show subpopulations

Gnomad4 AFR exome

AF:

0.102

Gnomad4 AMR exome

AF:

0.252

Gnomad4 ASJ exome

AF:

0.409

Gnomad4 EAS exome

AF:

0.212

Gnomad4 SAS exome

AF:

0.140

Gnomad4 FIN exome

AF:

0.440

Gnomad4 NFE exome

AF:

0.358

Gnomad4 OTH exome

AF:

0.314

GnomAD4 genome

AF:

0.276

AC:

41914

AN:

152060

Hom.:

6874

Cov.:

AF XY:

0.277

AC XY:

20558

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.110

Gnomad4 AMR

AF:

0.278

Gnomad4 ASJ

AF:

0.409

Gnomad4 EAS

AF:

0.191

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.442

Gnomad4 NFE

AF:

0.357

Gnomad4 OTH

AF:

0.311

Alfa

AF:

0.329

Hom.:

11331

Bravo

AF:

0.260

Asia WGS

AF:

0.148

AC:

520

AN:

3478

EpiCase

AF:

0.366

EpiControl

AF:

0.362

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Immunodeficiency, common variable, 3

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:1

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 47% of patients studied by a panel of primary immunodeficiencies. Number of patients: 45. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.19

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over