rs151093663
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1PM2PP5BS1_Supporting
The NM_001006658.3(CR2):c.2298G>A(p.Trp766*) 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
Consequence
NM_001006658.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000631 AC: 96AN: 152078Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000749 AC: 188AN: 251058Hom.: 1 AF XY: 0.000774 AC XY: 105AN XY: 135680
GnomAD4 exome AF: 0.000908 AC: 1326AN: 1460902Hom.: 1 Cov.: 30 AF XY: 0.000905 AC XY: 658AN XY: 726802
GnomAD4 genome AF: 0.000631 AC: 96AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37AN XY: 74414
ClinVar
Submissions by phenotype
not provided Pathogenic:5Uncertain:1
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. -
PP4, PS3_supporting, PS4_supporting, PVS1 -
Published functional studies suggest a damaging effect on B-cell receptor stimulation (PMID: 22035880); 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; This variant is associated with the following publications: (PMID: 30075290, Lougaris2020[Review Article], 34426522, Tang2022[case report], 31345219, 22035880, 38817346) -
- -
- -
- -
Immunodeficiency, common variable, 7 Pathogenic:3
- -
- -
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 gene product 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at