rs151093663

chr1-207474298-G-Achr1-207474298-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001006658.3(CR2):c.2298G>A(p.Trp766Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000882 in 1,613,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (1 hom.)
• Consequence: CR2 NM_001006658.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-207474298-G-A is Pathogenic according to our data. Variant chr1-207474298-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473097.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Likely_pathogenic=3, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3	c.2298G>A	p.Trp766Ter	stop_gained	13/20	ENST00000367057.8
CR2	NM_001877.5	c.2121G>A	p.Trp707Ter	stop_gained	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8	c.2298G>A	p.Trp766Ter	stop_gained	13/20	1	NM_001006658.3	P1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000749 AC: 188 AN: 251058 Hom.: 1 AF XY: 0.000774 AC XY: 105 AN XY: 135680

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000908 AC: 1326 AN: 1460902 Hom.: 1 Cov.: 30 AF XY: 0.000905 AC XY: 658 AN XY: 726802

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000631 AC: 96 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74414

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000918 Hom.: 0

Bravo AF: 0.000555

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000972 AC: 118

EpiCase AF: 0.000546

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:5 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Mar 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 12, 2023	PP4, PS3_supporting, PS4_supporting, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 11, 2017	The p.Trp766Ter variant, and c.1225+1G>C variant in compound heterozygous form, were previously reported in a 28-year old man with childhood history of recurrent respiratory tract infections, intermittent 20 years of no health concerns, and recent persistent myalgias, fevers, sore throat, chronic diarrhea as well as recurrent respiratory tract infections, splenomegaly, hypogammaglobulinemia and no expression of CD21 surface protein (Thiel 2012). Additionally, no mRNA expression was found for p.Trp766Ter and carrier mother had reduced copy number of mRNA with this variant. Furthermore, no CD21 expression was found in vitro in 293T cells with p.Trp766Ter variant (Thiel 2012). This variant is listed in the genome Aggregation Database (gnomAD) with a European (Non-Finnish) population frequency of 0.15 percent (identified on 188 out of 126,374 chromosomes including 1 homozygote). Of note, Wentink et al. (2015) described an asymptomatic 13 year old individual with hypogammaglobulinemia and two loss-of-function CR2 variants. Thus, it is conceivable that individuals with milder immunological and clinical phenotype and homozygous loss-of function CR2 variants may have their data included in gnomAD database. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2023	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies suggest a damaging effect on B-cell receptor stimulation (Thiel et al., 2012); This variant is associated with the following publications: (PMID: 30075290, Lougaris2020[Review Article], 22035880, 34426522, Tang2022[case report], 31345219) -

Immunodeficiency, common variable, 7 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 15, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Oct 23, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Trp766*) in the CR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CR2 are known to be pathogenic (PMID: 26325596, 28499783). This variant is present in population databases (rs151093663, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with hypogammaglobulinemia (PMID: 22035880). ClinVar contains an entry for this variant (Variation ID: 473097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CR2 function (PMID: 22035880). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.82	D
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.88
GERP RS		5.7

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

Other links and lift over

dbSNP: rs151093663; hg19: chr1-207647643;