1-207472877-G-A

Position:

chr1-207472877-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001006658.3(CR2):c.1676G>A(p.Gly559Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000625 in 1,613,946 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00062 ( 4 hom. )

Consequence

CR2
NM_001006658.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 2.68

Variant links:

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]

CR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.026024222).

BP6

Variant 1-207472877-G-A is Benign according to our data. Variant chr1-207472877-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 449008.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000625 (913/1461750) while in subpopulation MID AF= 0.0132 (76/5764). AF 95% confidence interval is 0.0108. There are 4 homozygotes in gnomad4_exome. There are 475 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR2	NM_001006658.3 linkuse as main transcript	c.1676G>A	p.Gly559Glu	missense_variant	10/20	ENST00000367057.8	NP_001006659.1
CR2	NM_001877.5 linkuse as main transcript	c.1676G>A	p.Gly559Glu	missense_variant	10/19		NP_001868.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR2	ENST00000367057.8 linkuse as main transcript	c.1676G>A	p.Gly559Glu	missense_variant	10/20	1	NM_001006658.3	ENSP00000356024	P1	P20023-3

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000848

AC:

213

AN:

251304

Hom.:

AF XY:

0.000781

AC XY:

106

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00873

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000853

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000625

AC:

913

AN:

1461750

Hom.:

Cov.:

AF XY:

0.000653

AC XY:

475

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00861

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000437

Gnomad4 OTH exome

AF:

0.00126

GnomAD4 genome

AF:

0.000631

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.000725

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000774

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Immunodeficiency, common variable, 7

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 04, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2017	The G559E variant in the CR2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G559E variant is observed in 79/66693 (0.118%) alleles from individuals of non-Finnish European background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G559E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret G559E as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CR2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Uncertain

0.076

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.85

D;D;D

M_CAP

Benign

0.041

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

2.9

M;M;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.42

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.025

D;D;D

Sift4G

Uncertain

0.028

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.46

MVP

0.95

MPC

0.77

ClinPred

0.077

GERP RS

4.7

Varity_R

0.26

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over