rs147263584

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001006658.3(CR2):​c.2506C>T​(p.Pro836Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CR2
NM_001006658.3 missense

Scores

5
12
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.65
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CR2NM_001006658.3 linkuse as main transcriptc.2506C>T p.Pro836Ser missense_variant 14/20 ENST00000367057.8 NP_001006659.1
CR2NM_001877.5 linkuse as main transcriptc.2329C>T p.Pro777Ser missense_variant 13/19 NP_001868.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CR2ENST00000367057.8 linkuse as main transcriptc.2506C>T p.Pro836Ser missense_variant 14/201 NM_001006658.3 ENSP00000356024 P1P20023-3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251104
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135708
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000969
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000588
AC:
86
AN:
1461800
Hom.:
0
Cov.:
32
AF XY:
0.0000605
AC XY:
44
AN XY:
727210
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000737
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74342
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000901
Hom.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 7 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 28, 2021This sequence change replaces proline with serine at codon 836 of the CR2 protein (p.Pro836Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs147263584, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with CR2-related conditions. 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: "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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Uncertain
0.083
D
BayesDel_noAF
Uncertain
0.090
CADD
Benign
21
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.63
D;.;.
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.86
D;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.90
D;D;D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Pathogenic
3.9
H;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.33
T
PROVEAN
Pathogenic
-6.5
D;D;D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
D;D;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.55
MVP
0.93
MPC
0.69
ClinPred
0.98
D
GERP RS
4.8
Varity_R
0.72
gMVP
0.99

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.

Other links and lift over

dbSNP: rs147263584; hg19: chr1-207648351; COSMIC: COSV65508885; COSMIC: COSV65508885; API