rs17617

chr1-207480050-C-Achr1-207480050-C-Gchr1-207480050-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001006658.3(CR2):c.3185C>A(p.Ala1062Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,608,866 control chromosomes in the GnomAD database, including 597,269 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60237 hom., cov: 32)
  • Exomes 𝑓: 0.86 (537032 hom.)
• Consequence: CR2 NM_001006658.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.173

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.1627176E-7).
• BP6: Variant 1-207480050-C-A is Benign according to our data. Variant chr1-207480050-C-A is described in ClinVar as [Benign]. Clinvar id is 402562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207480050-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3	c.3185C>A	p.Ala1062Glu	missense_variant	18/20	ENST00000367057.8
CR2	NM_001877.5	c.3008C>A	p.Ala1003Glu	missense_variant	17/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8	c.3185C>A	p.Ala1062Glu	missense_variant	18/20	1	NM_001006658.3	P1

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134882 AN: 152116 Hom.: 60181 Cov.: 32

Gnomad AFR AF: 0.972

Gnomad AMI AF: 0.799

Gnomad AMR AF: 0.878

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.926

Gnomad FIN AF: 0.859

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.834

Gnomad OTH AF: 0.879

GnomAD3 exomes AF: 0.882 AC: 221217 AN: 250948 Hom.: 98033 AF XY: 0.878 AC XY: 119056 AN XY: 135642

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.916

Gnomad ASJ exome AF: 0.827

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.922

Gnomad FIN exome AF: 0.858

Gnomad NFE exome AF: 0.838

Gnomad OTH exome AF: 0.859

GnomAD4 exome AF: 0.858 AC: 1249093 AN: 1456632 Hom.: 537032 Cov.: 33 AF XY: 0.858 AC XY: 622065 AN XY: 724876

Gnomad4 AFR exome AF: 0.979

Gnomad4 AMR exome AF: 0.914

Gnomad4 ASJ exome AF: 0.831

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.920

Gnomad4 FIN exome AF: 0.858

Gnomad4 NFE exome AF: 0.842

Gnomad4 OTH exome AF: 0.865

GnomAD4 genome AF: 0.887 AC: 134997 AN: 152234 Hom.: 60237 Cov.: 32 AF XY: 0.889 AC XY: 66171 AN XY: 74428

Gnomad4 AFR AF: 0.972

Gnomad4 AMR AF: 0.878

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.925

Gnomad4 FIN AF: 0.859

Gnomad4 NFE AF: 0.834

Gnomad4 OTH AF: 0.880

Alfa AF: 0.845 Hom.: 99800

Bravo AF: 0.893

TwinsUK AF: 0.849 AC: 3147

ALSPAC AF: 0.844 AC: 3251

ESP6500AA AF: 0.976 AC: 4299

ESP6500EA AF: 0.829 AC: 7127

ExAC AF: 0.883 AC: 107250

Asia WGS AF: 0.967 AC: 3361 AN: 3478

EpiCase AF: 0.829

EpiControl AF: 0.840

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, 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: Frequency -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 98% of patients studied by a panel of primary immunodeficiencies. Number of patients: 93. Only high quality variants are reported. -

Immunodeficiency, common variable, 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.81
Dann	Benign	0.27
DEOGEN2	Benign	0.099	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.15	T;T;T
MetaRNN	Benign	7.2e-7	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	1.4	N;N;N
REVEL	Benign	0.063
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.064
MPC		0.19
ClinPred		0.00086	T
GERP RS		-2.1
Varity_R		0.068
gMVP		0.49

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: rs17617; hg19: chr1-207653395; COSMIC: COSV65507634;