chr1-207474298-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PVS1PS3PP5

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). ClinVar reports functional evidence for this variant: "SCV000652484: Experimental studies have shown that this premature translational stop signal affects CR2 function (PMID:22035880)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 1 hom. )

Consequence

CR2
NM_001006658.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:1

Conservation

PhyloP100: 4.19

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency, common variable, 7
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
common variable immunodeficiency
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

CR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000652484: Experimental studies have shown that this premature translational stop signal affects CR2 function (PMID: 22035880).; SCV000885264: Furthermore, no CD21 expression was found in vitro in 293T cells with p.Trp766Ter variant (Thiel 2012).; SCV000890334: Published functional studies suggest a damaging effect on B-cell receptor stimulation (PMID: 22035880);

PP5

Variant 1-207474298-G-A is Pathogenic according to our data. Variant chr1-207474298-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473097.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006658.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	NM_001006658.3	MANE Select	c.2298G>A	p.Trp766*	stop_gained	Exon 13 of 20	NP_001006659.1	P20023-3
	CR2	NM_001877.5		c.2121G>A	p.Trp707*	stop_gained	Exon 12 of 19	NP_001868.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CR2	ENST00000367057.8	TSL:1 MANE Select	c.2298G>A	p.Trp766*	stop_gained	Exon 13 of 20	ENSP00000356024.3	P20023-3
CR2	ENST00000367058.7	TSL:1	c.2121G>A	p.Trp707*	stop_gained	Exon 12 of 19	ENSP00000356025.3	P20023-1
CR2	ENST00000367059.3	TSL:1	c.2121G>A	p.Trp707*	stop_gained	Exon 12 of 18	ENSP00000356026.3	Q5SR47

Frequencies

GnomAD3 genomes

AF:

0.000631

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00116

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000749

AC:

188

AN:

251058

AF XY:

0.000774

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000908

AC:

1326

AN:

1460902

Hom.:

Cov.:

AF XY:

0.000905

AC XY:

658

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33440

American (AMR)

AF:

0.0000895

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.000243

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00114

AC:

1271

AN:

1111236

Other (OTH)

AF:

0.000547

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

128

193

257

321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000631

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41522

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00116

AC:

AN:

68000

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000996

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000972

AC:

118

EpiCase

AF:

0.000546

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Immunodeficiency, common variable, 7 (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.82

PhyloP100

4.2

Vest4

0.88

GERP RS

5.7

Mutation Taster

=11/189

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over