chr16-28933075-C-G

Variant names:

• chr16-28933075-C-G
• rs2904880
• NM_001770.6:c.520C>G

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.146
• Publications: 64 publications found

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001770.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD19	NM_001770.6	MANE Select	c.520C>G	p.Leu174Val	missense	Exon 3 of 15	NP_001761.3
	CD19	NM_001178098.2		c.520C>G	p.Leu174Val	missense	Exon 3 of 15	NP_001171569.1	P15391-2
	CD19	NM_001385732.1		c.253C>G	p.Leu85Val	missense	Exon 2 of 14	NP_001372661.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CD19	ENST00000538922.8	TSL:5 MANE Select	c.520C>G	p.Leu174Val	missense	Exon 3 of 15	ENSP00000437940.2	P15391-1
	CD19	ENST00000324662.8	TSL:1	c.520C>G	p.Leu174Val	missense	Exon 3 of 15	ENSP00000313419.4	P15391-2
	RABEP2	ENST00000566762.1	TSL:4	c.-150+3189G>C		intron	N/A	ENSP00000454974.1	H3BNR8

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

GnomAD2 exomes AF: 0.719 AC: 179615 AN: 249700 AF XY: 0.725

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.: 55 AF XY: 0.701 AC XY: 509168 AN XY: 726728

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

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

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

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Immunodeficiency, common variable, 3 (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.13	T
MetaRNN	Benign	7.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.15
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.072
Sift	Benign	0.20	T
Sift4G	Benign	0.14	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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