Genetic Variant CR2:p.Pro208Pro (chr1-207468705-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001006658.3(CR2):c.624C>G(p.Pro208Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,976 control chromosomes in the GnomAD database, including 140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P208P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0091 ( 9 hom., cov: 32)

Exomes 𝑓: 0.011 ( 131 hom. )

Consequence

CR2
NM_001006658.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.81

Publications

7 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 1-207468705-C-G is Benign according to our data. Variant chr1-207468705-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 439556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.82 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00911 (1387/152254) while in subpopulation NFE AF = 0.0118 (800/68008). AF 95% confidence interval is 0.0111. There are 9 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 Unknown,AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	NM_001006658.3	MANE Select	c.624C>G	p.Pro208Pro	synonymous	Exon 3 of 20	NP_001006659.1
	CR2	NM_001877.5		c.624C>G	p.Pro208Pro	synonymous	Exon 3 of 19	NP_001868.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CR2	ENST00000367057.8	TSL:1 MANE Select	c.624C>G	p.Pro208Pro	synonymous	Exon 3 of 20	ENSP00000356024.3
CR2	ENST00000367058.7	TSL:1	c.624C>G	p.Pro208Pro	synonymous	Exon 3 of 19	ENSP00000356025.3
CR2	ENST00000367059.3	TSL:1	c.624C>G	p.Pro208Pro	synonymous	Exon 3 of 18	ENSP00000356026.3

Frequencies

GnomAD3 genomes

AF:

0.00912

AC:

1387

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00237

Gnomad AMI

AF:

0.0220

Gnomad AMR

AF:

0.00485

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0294

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0118

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00901

AC:

2264

AN:

251408

AF XY:

0.00904

show subpopulations

Gnomad AFR exome

AF:

0.00209

Gnomad AMR exome

AF:

0.00434

Gnomad ASJ exome

AF:

0.0150

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0240

Gnomad NFE exome

AF:

0.0113

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.0114

AC:

16603

AN:

1461722

Hom.:

131

Cov.:

AF XY:

0.0111

AC XY:

8097

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00158

AC:

AN:

33458

American (AMR)

AF:

0.00420

AC:

188

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

417

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00211

AC:

182

AN:

86258

European-Finnish (FIN)

AF:

0.0220

AC:

1173

AN:

53414

Middle Eastern (MID)

AF:

0.00711

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0125

AC:

13930

AN:

1111898

Other (OTH)

AF:

0.0102

AC:

617

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

963

1926

2890

3853

4816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.00911

AC:

1387

AN:

152254

Hom.:

Cov.:

AF XY:

0.00998

AC XY:

743

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41556

American (AMR)

AF:

0.00484

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00290

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0294

AC:

312

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0118

AC:

800

AN:

68008

Other (OTH)

AF:

0.00758

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00695

Hom.:

Bravo

AF:

0.00735

EpiCase

AF:

0.0115

EpiControl

AF:

0.0117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CR2: BP4, BP7, BS1, BS2

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Immunodeficiency, common variable, 7

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CR2-related disorder

Benign:1

Mar 04, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Systemic lupus erythematosus, susceptibility to, 9;C3150354:Immunodeficiency, common variable, 2;C3542922:Immunodeficiency, common variable, 7

Benign:1

Apr 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.53

(source)

DANN

Benign

0.50

PhyloP100

-2.8

Mutation Taster

=99/1

polymorphism

(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

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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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over