rs17615

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001006658.3(CR2):c.1916G>A(p.Ser639Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 1,613,598 control chromosomes in the GnomAD database, including 76,631 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. S639R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.30 ( 7260 hom., cov: 32)

Exomes 𝑓: 0.30 ( 69371 hom. )

Consequence

CR2
NM_001006658.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.364

Publications

57 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.042719E-4).

BP6

Variant 1-207473117-G-A is Benign according to our data. Variant chr1-207473117-G-A is described in ClinVar as Benign. ClinVar VariationId is 402559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR2	NM_001006658.3 link	c.1916G>A	p.Ser639Asn	missense_variant	Exon 10 of 20	ENST00000367057.8	NP_001006659.1	P20023-3
CR2	NM_001877.5 link	c.1916G>A	p.Ser639Asn	missense_variant	Exon 10 of 19		NP_001868.2	P20023-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR2	ENST00000367057.8 link	c.1916G>A	p.Ser639Asn	missense_variant	Exon 10 of 20	1	NM_001006658.3	ENSP00000356024.3		P20023-3

Frequencies

GnomAD3 genomes

AF:

0.302

AC:

45870

AN:

151978

Hom.:

7248

Cov.:

show subpopulations

Gnomad AFR

AF:

0.377

Gnomad AMI

AF:

0.206

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.277

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.218

Gnomad FIN

AF:

0.228

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.309

Gnomad OTH

AF:

0.292

GnomAD2 exomes

AF:

0.261

AC:

65486

AN:

251076

AF XY:

0.262

show subpopulations

Gnomad AFR exome

AF:

0.387

Gnomad AMR exome

AF:

0.162

Gnomad ASJ exome

AF:

0.281

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.311

Gnomad OTH exome

AF:

0.277

GnomAD4 exome

AF:

0.303

AC:

442132

AN:

1461502

Hom.:

69371

Cov.:

AF XY:

0.300

AC XY:

218196

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.380

AC:

12696

AN:

33454

American (AMR)

AF:

0.171

AC:

7635

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

7443

AN:

26128

East Asian (EAS)

AF:

0.121

AC:

4817

AN:

39694

South Asian (SAS)

AF:

0.224

AC:

19342

AN:

86244

European-Finnish (FIN)

AF:

0.230

AC:

12308

AN:

53404

Middle Eastern (MID)

AF:

0.311

AC:

1793

AN:

5764

European-Non Finnish (NFE)

AF:

0.322

AC:

358538

AN:

1111752

Other (OTH)

AF:

0.291

AC:

17560

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17966

35932

53897

71863

89829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11680

23360

35040

46720

58400

<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:

0.302

AC:

45916

AN:

152096

Hom.:

7260

Cov.:

AF XY:

0.295

AC XY:

21934

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.377

AC:

15649

AN:

41478

American (AMR)

AF:

0.223

AC:

3410

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.277

AC:

959

AN:

3466

East Asian (EAS)

AF:

0.107

AC:

553

AN:

5176

South Asian (SAS)

AF:

0.220

AC:

1063

AN:

4830

European-Finnish (FIN)

AF:

0.228

AC:

2408

AN:

10584

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.309

AC:

20985

AN:

67972

Other (OTH)

AF:

0.290

AC:

612

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1646

3291

4937

6582

8228

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<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:

0.304

Hom.:

34167

Bravo

AF:

0.305

TwinsUK

AF:

0.320

AC:

1187

ALSPAC

AF:

0.327

AC:

1260

ESP6500AA

AF:

0.380

AC:

1674

ESP6500EA

AF:

0.316

AC:

2714

ExAC

AF:

0.270

AC:

32807

Asia WGS

AF:

0.179

AC:

622

AN:

3478

EpiCase

AF:

0.303

EpiControl

AF:

0.308

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Immunodeficiency, common variable, 7

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.67

T;T;T

MetaRNN

Benign

0.00060

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

2.0

M;M;.

PhyloP100

0.36

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.25

T;T;T

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.087

MPC

0.50

ClinPred

0.020

GERP RS

4.8

Varity_R

0.13

gMVP

0.58

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Publications

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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