1-207468605-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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:4

Conservation

PhyloP100: 0.530

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 402563.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4}. Variant chr1-207468605-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3 linkuse as main transcript	c.524C>T	p.Pro175Leu	missense_variant	3/20	ENST00000367057.8
CR2	NM_001877.5 linkuse as main transcript	c.524C>T	p.Pro175Leu	missense_variant	3/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8 linkuse as main transcript	c.524C>T	p.Pro175Leu	missense_variant	3/20	1	NM_001006658.3	P1	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

GnomAD3 exomes

AF:

0.00432

AC:

1086

AN:

251348

Hom.:

AF XY:

0.00465

AC XY:

632

AN XY:

135828

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 SAS exome

AF:

0.00758

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

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00103

Gnomad4 ASJ exome

AF:

0.00394

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00802

Gnomad4 FIN exome

AF:

0.000618

Gnomad4 NFE exome

AF:

0.00737

Gnomad4 OTH exome

AF:

0.00480

GnomAD4 genome

AF:

0.00359

AC:

547

AN:

152290

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00140

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00727

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00603

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00549

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:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CR2: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 18, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 26, 2023	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) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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). -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 29, 2020

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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

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;.

MutationTaster

Benign

1.0

N;N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over