Genetic Variant CR2:c.446-32C>T (chr1-207468495-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001006658.3(CR2):c.446-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,609,610 control chromosomes in the GnomAD database, including 31,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2036 hom., cov: 32)

Exomes 𝑓: 0.20 ( 29483 hom. )

Consequence

CR2
NM_001006658.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.190

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 1-207468495-C-T is Benign according to our data. Variant chr1-207468495-C-T is described in ClinVar as Benign. ClinVar VariationId is 1263891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR2	NM_001006658.3 link	c.446-32C>T		intron_variant	Intron 2 of 19	ENST00000367057.8	NP_001006659.1	P20023-3
CR2	NM_001877.5 link	c.446-32C>T		intron_variant	Intron 2 of 18		NP_001868.2	P20023-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR2	ENST00000367057.8 link	c.446-32C>T		intron_variant	Intron 2 of 19	1	NM_001006658.3	ENSP00000356024.3		P20023-3

Frequencies

GnomAD3 genomes

AF:

0.158

AC:

24043

AN:

151976

Hom.:

2035

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0898

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.143

Gnomad ASJ

AF:

0.219

Gnomad EAS

AF:

0.106

Gnomad SAS

AF:

0.166

Gnomad FIN

AF:

0.167

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.201

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.169

AC:

42113

AN:

249188

AF XY:

0.173

show subpopulations

Gnomad AFR exome

AF:

0.0866

Gnomad AMR exome

AF:

0.114

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.166

Gnomad NFE exome

AF:

0.203

Gnomad OTH exome

AF:

0.197

GnomAD4 exome

AF:

0.197

AC:

287223

AN:

1457516

Hom.:

29483

Cov.:

AF XY:

0.197

AC XY:

142892

AN XY:

725212

show subpopulations

African (AFR)

AF:

0.0859

AC:

2866

AN:

33374

American (AMR)

AF:

0.119

AC:

5306

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

5709

AN:

26090

East Asian (EAS)

AF:

0.121

AC:

4796

AN:

39654

South Asian (SAS)

AF:

0.167

AC:

14405

AN:

86124

European-Finnish (FIN)

AF:

0.162

AC:

8638

AN:

53160

Middle Eastern (MID)

AF:

0.252

AC:

1443

AN:

5736

European-Non Finnish (NFE)

AF:

0.210

AC:

232490

AN:

1108522

Other (OTH)

AF:

0.192

AC:

11570

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

12608

25216

37824

50432

63040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8072

16144

24216

32288

40360

<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:

0.158

AC:

24058

AN:

152094

Hom.:

2036

Cov.:

AF XY:

0.156

AC XY:

11574

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0898

AC:

3728

AN:

41496

American (AMR)

AF:

0.143

AC:

2183

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

761

AN:

3472

East Asian (EAS)

AF:

0.106

AC:

550

AN:

5186

South Asian (SAS)

AF:

0.167

AC:

805

AN:

4818

European-Finnish (FIN)

AF:

0.167

AC:

1771

AN:

10584

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.201

AC:

13661

AN:

67942

Other (OTH)

AF:

0.182

AC:

384

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1029

2058

3088

4117

5146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.128

Hom.:

304

Bravo

AF:

0.155

Asia WGS

AF:

0.130

AC:

453

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.83

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over