rs17616

Positions:

• chr1-207473578-G-A
• chr1-207473578-G-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.2012G>A​(p.Arg671His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,611,296 control chromosomes in the GnomAD database, including 76,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R671C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (7231 hom., cov: 32)
  • Exomes 𝑓: 0.30 (68777 hom.)
• Consequence: CR2 NM_001006658.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.15

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=5.750954E-4).
• BP6: Variant 1-207473578-G-A is Benign according to our data. Variant chr1-207473578-G-A is described in ClinVar as [Benign]. Clinvar id is 402561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207473578-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3	c.2012G>A	p.Arg671His	missense_variant	11/20	ENST00000367057.8
CR2	NM_001877.5	c.1979-223G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8	c.2012G>A	p.Arg671His	missense_variant	11/20	1	NM_001006658.3	P1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45751 AN: 151956 Hom.: 7219 Cov.: 32

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.293

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.260 AC: 65155 AN: 251076 Hom.: 9223 AF XY: 0.260 AC XY: 35331 AN XY: 135690

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.220

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.308

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.301 AC: 439033 AN: 1459222 Hom.: 68777 Cov.: 42 AF XY: 0.299 AC XY: 216775 AN XY: 726054

Gnomad4 AFR exome AF: 0.379

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.321

Gnomad4 OTH exome AF: 0.290

GnomAD4 genome AF: 0.301 AC: 45797 AN: 152074 Hom.: 7231 Cov.: 32 AF XY: 0.294 AC XY: 21865 AN XY: 74338

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.223

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.220

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.289

Alfa AF: 0.302 Hom.: 17501

Bravo AF: 0.305

TwinsUK AF: 0.318 AC: 1178

ALSPAC AF: 0.325 AC: 1251

ESP6500AA AF: 0.379 AC: 1672

ESP6500EA AF: 0.315 AC: 2707

ExAC AF: 0.268 AC: 32589

Asia WGS AF: 0.179 AC: 622 AN: 3478

EpiCase AF: 0.302

EpiControl AF: 0.307

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 34% of patients studied by a panel of primary immunodeficiencies. Number of patients: 32. Only high quality variants are reported. -

Immunodeficiency, common variable, 7 Benign:2

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.043
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.00058	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.25
Sift	Benign	0.19	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.13
MPC		0.69
ClinPred		0.039	T
GERP RS		-8.6
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs17616; hg19: chr1-207646923; COSMIC: COSV65506628; COSMIC: COSV65506628;