16-28933379-G-T

Variant names:

• chr16-28933379-G-T
• rs35979293
• NM_001770.6:c.705G>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.29

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 -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 rank	MANE	Protein	UniProt
CD19	NM_001770.6	c.705G>T	p.Pro235Pro	synonymous_variant	Exon 4 of 15	ENST00000538922.8	NP_001761.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD19	ENST00000538922.8	c.705G>T	p.Pro235Pro	synonymous_variant	Exon 4 of 15	5	NM_001770.6	ENSP00000437940.2

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41925 AN: 151942 Hom.: 6876 Cov.: 31

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

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.: 47 AF XY: 0.329 AC XY: 239309 AN XY: 727194

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.: 31 AF XY: 0.277 AC XY: 20558 AN XY: 74318

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

Submissions by phenotype

not provided Benign:3

-

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

- -

Nov 10, 2018

GeneDx

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. -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

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 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

Other links and lift over

dbSNP: rs35979293; hg19: chr16-28944700; COSMIC: COSV61188690; COSMIC: COSV61188690;