chr1-207468605-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001006658.3(CR2):c.524C>T(p.Pro175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,614,062 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P175S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 47 hom. )

Consequence

CR2
NM_001006658.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 0.530

Publications

13 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020729423).

BP6

Variant 1-207468605-C-T is Benign according to our data. Variant chr1-207468605-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402563.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00359 (547/152290) while in subpopulation SAS AF = 0.00727 (35/4816). AF 95% confidence interval is 0.00555. There are 1 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 47 Unknown,AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR2	NM_001006658.3 link	c.524C>T	p.Pro175Leu	missense_variant	Exon 3 of 20	ENST00000367057.8	NP_001006659.1	P20023-3
CR2	NM_001877.5 link	c.524C>T	p.Pro175Leu	missense_variant	Exon 3 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.524C>T	p.Pro175Leu	missense_variant	Exon 3 of 20	1	NM_001006658.3	ENSP00000356024.3		P20023-3

Frequencies

GnomAD3 genomes

AF:

0.00359

AC:

546

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00603

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00432

AC:

1086

AN:

251348

AF XY:

0.00465

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.000868

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00641

Gnomad OTH exome

AF:

0.00408

GnomAD4 exome

AF:

0.00645

AC:

9431

AN:

1461772

Hom.:

Cov.:

AF XY:

0.00649

AC XY:

4718

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33466

American (AMR)

AF:

0.00103

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00394

AC:

103

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00802

AC:

692

AN:

86258

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00737

AC:

8191

AN:

1111942

Other (OTH)

AF:

0.00480

AC:

290

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

556

1111

1667

2222

2778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

334

668

1002

1336

1670

<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:

0.00359

AC:

547

AN:

152290

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41558

American (AMR)

AF:

0.00196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00727

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00603

AC:

410

AN:

68020

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

108

135

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:

0.00516

Hom.:

Bravo

AF:

0.00379

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00744

AC:

ExAC

AF:

0.00448

AC:

544

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 26, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in one individual from a cohort of patients with atypical hemolytic uremic syndrome and this individual also possessed a variant in another gene (Bu et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 24029428) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CR2: BP4, BS1, BS2 -

Nov 18, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

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: 0.7% in East asian in ExAC with 2 homozygotes and 0.58% in european with 1 homozygote. Reported in 1/36 patients with hemolytic syndrome who also carried a c.1160-2A>G variant in CFH (Bu 2014). However, even the association gene-disease is not that strong (moderate). -

Oct 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CR2 c.524C>T (p.Pro175Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0043 in 251348 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in CR2 causing Immunodeficiency, Common Variable, 7 phenotype. c.524C>T has been reported in the literature in unspecified individuals affected with Atypical hemolytic uremic syndrome, without strong evidence for causality (Bu_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Immunodeficiency, Common Variable, 7. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24029428). ClinVar contains an entry for this variant (Variation ID: 402563). Based on the evidence outlined above, the variant was classified as likely benign. -

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

CR2 NM_001006658.2 exon 3 p.Pro175Leu (c.524C>T): This variant has been reported in the literature in 1 individual with atypical hemolytic uremic syndrome (aHUS) (Bu 2014 PMID:24029428). This variant is present in 0.6% (410/68028) of European alleles including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-207468605-C-T?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Benign (Variation ID:402563). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

CR2-related disorder

Benign:1

May 29, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Immunodeficiency, common variable, 7

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.23

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.074

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.5

L;L;.

PhyloP100

0.53

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Pathogenic

0.67

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.89

P;D;D

Vest4

0.39

MVP

0.81

MPC

0.52

ClinPred

0.033

GERP RS

4.9

Varity_R

0.072

gMVP

0.59

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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