rs145499318

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001006658.3(CR2):c.3187C>T(p.Arg1063Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,607,614 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00060 ( 3 hom. )

Consequence

CR2
NM_001006658.3 missense, splice_region

Scores

Splicing: ADA: 0.003550

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 0.499

Publications

5 publications found

Variant links:

Genes affected

CR2 (HGNC:2336): (complement C3d receptor 2) This gene encodes a membrane protein, which functions as a receptor for Epstein-Barr virus (EBV) binding on B and T lymphocytes. Genetic variations in this gene are associated with susceptibility to systemic lupus erythematosus type 9 (SLEB9). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

CR2 Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 7
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

CR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16642961).

BS2

High Homozygotes in GnomAdExome4 at 3 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR2	NM_001006658.3 link	c.3187C>T	p.Arg1063Cys	missense_variant, splice_region_variant	Exon 18 of 20	ENST00000367057.8	NP_001006659.1
CR2	NM_001877.5 link	c.3010C>T	p.Arg1004Cys	missense_variant, splice_region_variant	Exon 17 of 19		NP_001868.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR2	ENST00000367057.8 link	c.3187C>T	p.Arg1063Cys	missense_variant, splice_region_variant	Exon 18 of 20	1	NM_001006658.3	ENSP00000356024.3

Frequencies

GnomAD3 genomes

AF:

0.000427

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000470

AC:

118

AN:

251022

AF XY:

0.000545

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000643

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000597

AC:

869

AN:

1455362

Hom.:

Cov.:

AF XY:

0.000595

AC XY:

431

AN XY:

724406

show subpopulations

African (AFR)

AF:

0.0000902

AC:

AN:

33254

American (AMR)

AF:

0.000313

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26072

East Asian (EAS)

AF:

0.000101

AC:

AN:

39638

South Asian (SAS)

AF:

0.000929

AC:

AN:

86106

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000654

AC:

723

AN:

1106342

Other (OTH)

AF:

0.000598

AC:

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000427

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41542

American (AMR)

AF:

0.000523

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68012

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000682

Hom.:

Bravo

AF:

0.000397

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000494

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 7

Uncertain:3

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1063 of the CR2 protein (p.Arg1063Cys). This variant is present in population databases (rs145499318, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immune deficiency (CVID) and decreased memory B cells with an exhausted B cell phenotype (CD21dim) (Invitae). ClinVar contains an entry for this variant (Variation ID: 540312). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 20, 2019

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CR2 NM_001006658.2 exon 18 p.Arg1063Cys (c.3187C>T): This variant has not been reported in the literature but is present in 0.09% (28/30602) of South Asian alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/1-207653397-C-T). This variant is present in ClinVar (Variation ID:540312). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3187C>T (p.R1063C) alteration is located in exon 18 (coding exon 18) of the CR2 gene. This alteration results from a C to T substitution at nucleotide position 3187, causing the arginine (R) at amino acid position 1063 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CR2-related disorder

Uncertain:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CR2 c.3187C>T variant is predicted to result in the amino acid substitution p.Arg1063Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.091% of alleles in individuals of South Asian descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/1-207653397-C-T). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Systemic lupus erythematosus, susceptibility to, 9;C3542922:Immunodeficiency, common variable, 7

Uncertain:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;.;.

Eigen

Benign

0.0038

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

N;.;.

PhyloP100

0.50

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0090

D;T;D

Polyphen

1.0

D;D;D

Vest4

0.45

MVP

0.67

MPC

0.73

ClinPred

0.067

GERP RS

1.6

Varity_R

0.11

gMVP

0.50

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0036

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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