rs34763945

Variant names:

• chr16-28938730-G-A
• rs34763945
• NM_001770.6:c.1541G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-28938730-G-A
• chr16-28938730-G-T

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.445
• Publications: 17 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]

CD19 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 VariationId 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.

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.1541G>A	p.Arg514His	missense	Exon 13 of 15	NP_001761.3
	CD19	NM_001178098.2		c.1544G>A	p.Arg515His	missense	Exon 13 of 15	NP_001171569.1	P15391-2
	CD19	NM_001385732.1		c.1274G>A	p.Arg425His	missense	Exon 12 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.1541G>A	p.Arg514His	missense	Exon 13 of 15	ENSP00000437940.2	P15391-1
	CD19	ENST00000324662.8	TSL:1	c.1544G>A	p.Arg515His	missense	Exon 13 of 15	ENSP00000313419.4	P15391-2
	CD19	ENST00000565089.5	TSL:2	n.1975G>A		non_coding_transcript_exon	Exon 11 of 13

Frequencies

GnomAD3 genomes AF: 0.0402 AC: 6118 AN: 152092 Hom.: 174 Cov.: 31

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

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.: 33 AF XY: 0.0571 AC XY: 41519 AN XY: 727106

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: 4 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

GnomAD4 genome AF: 0.0402 AC: 6123 AN: 152210 Hom.: 174 Cov.: 31 AF XY: 0.0393 AC XY: 2922 AN XY: 74404

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: 78 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 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: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0626 AC: 4260 AN: 68008

Other (OTH) AF: 0.0388 AC: 82 AN: 2114

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: 62

ESP6500EA AF: 0.0643 AC: 553

ExAC AF: 0.0398 AC: 4827

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0612

EpiControl AF: 0.0577

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Immunodeficiency, common variable, 3 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.45
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.019
Sift	Benign	0.18	T
Sift4G	Benign	0.088	T
Polyphen		0.20	B
Vest4		0.070
MPC		0.31
ClinPred		0.025	T
GERP RS		0.66
Varity_R		0.051
Mutation Taster		=99/1	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: rs34763945; hg19: chr16-28950051; COSMIC: COSV61187809; COSMIC: COSV61187809;