rs148388565

chr1-207470087-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001006658.3(CR2):c.1210C>G(p.Pro404Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000781 in 1,613,586 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00083 ( 1 hom. )

Consequence

CR2
NM_001006658.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 4.43

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3 linkuse as main transcript	c.1210C>G	p.Pro404Ala	missense_variant	6/20	ENST00000367057.8
CR2	NM_001877.5 linkuse as main transcript	c.1210C>G	p.Pro404Ala	missense_variant	6/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8 linkuse as main transcript	c.1210C>G	p.Pro404Ala	missense_variant	6/20	1	NM_001006658.3	P1	P20023-3

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000632

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000319

AC:

AN:

250760

Hom.:

AF XY:

0.000369

AC XY:

AN XY:

135518

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000645

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000829

AC:

1211

AN:

1461394

Hom.:

Cov.:

AF XY:

0.000813

AC XY:

591

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00103

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000329

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000632

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000582

Hom.:

Bravo

AF:

0.000295

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000280

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 7

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 12, 2022	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 404 of the CR2 protein (p.Pro404Ala). This variant is present in population databases (rs148388565, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 578201). 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: "Deleterious"; PolyPhen-2: "Probably 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2018

- -

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 6 p.Pro404Ala (c.1210C>G): This variant has not been reported in the literature but is present in 0.6% (82/128630) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-207643432-C-G). This variant is present in ClinVar (Variation ID:578201). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Systemic lupus erythematosus, susceptibility to, 9;C3150354:Immunodeficiency, common variable, 2;C3542922:Immunodeficiency, common variable, 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

-0.070

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Pathogenic

3.1

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.36

PROVEAN

Pathogenic

-7.0

D;D;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.032

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.64

MVP

0.91

MPC

0.68

ClinPred

0.79

GERP RS

5.1

Varity_R

0.56

gMVP

0.75

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

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