rs1048971

Positions:

• chr1-207472977-G-A
• chr1-207472977-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001006658.3(CR2):​c.1776G>A​(p.Leu592=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,613,704 control chromosomes in the GnomAD database, including 112,939 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (16050 hom., cov: 32)
  • Exomes 𝑓: 0.36 (96889 hom.)
• Consequence: CR2 NM_001006658.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.522

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-207472977-G-A is Benign according to our data. Variant chr1-207472977-G-A is described in ClinVar as [Benign]. Clinvar id is 402558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207472977-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.522 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR2	NM_001006658.3	c.1776G>A	p.Leu592=	synonymous_variant	10/20	ENST00000367057.8	NP_001006659.1
CR2	NM_001877.5	c.1776G>A	p.Leu592=	synonymous_variant	10/19		NP_001868.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR2	ENST00000367057.8	c.1776G>A	p.Leu592=	synonymous_variant	10/20	1	NM_001006658.3	ENSP00000356024	P1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65232 AN: 151896 Hom.: 16008 Cov.: 32

Gnomad AFR AF: 0.689

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.429

GnomAD3 exomes AF: 0.336 AC: 84508 AN: 251168 Hom.: 15868 AF XY: 0.333 AC XY: 45137 AN XY: 135734

Gnomad AFR exome AF: 0.704

Gnomad AMR exome AF: 0.229

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.287

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.341

GnomAD4 exome AF: 0.357 AC: 521943 AN: 1461690 Hom.: 96889 Cov.: 55 AF XY: 0.354 AC XY: 257493 AN XY: 727136

Gnomad4 AFR exome AF: 0.705

Gnomad4 AMR exome AF: 0.239

Gnomad4 ASJ exome AF: 0.304

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.289

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.430 AC: 65330 AN: 152014 Hom.: 16050 Cov.: 32 AF XY: 0.422 AC XY: 31331 AN XY: 74308

Gnomad4 AFR AF: 0.689

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.209

Gnomad4 SAS AF: 0.287

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.425

Alfa AF: 0.360 Hom.: 10766

Bravo AF: 0.442

Asia WGS AF: 0.264 AC: 917 AN: 3478

EpiCase AF: 0.350

EpiControl AF: 0.356

ClinVar

Significance: Benign

Submissions summary: Benign:6

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 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

Immunodeficiency, common variable, 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.63
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1048971; hg19: chr1-207646322; COSMIC: COSV65506619; COSMIC: COSV65506619;