chr1-207473572-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001006658.3(CR2):c.2006A>G(p.His669Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,613,894 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H669H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 4 hom. )

Consequence

CR2
NM_001006658.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.755

Publications

2 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030501753).

BP6

Variant 1-207473572-A-G is Benign according to our data. Variant chr1-207473572-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540322.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000313 (458/1461590) while in subpopulation MID AF = 0.00226 (13/5762). AF 95% confidence interval is 0.00133. There are 4 homozygotes in GnomAdExome4. There are 240 alleles in the male GnomAdExome4 subpopulation. Median coverage is 41. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	NM_001006658.3	MANE Select	c.2006A>G	p.His669Arg	missense	Exon 11 of 20	NP_001006659.1	P20023-3
	CR2	NM_001877.5		c.1979-229A>G		intron	N/A	NP_001868.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CR2	ENST00000367057.8	TSL:1 MANE Select	c.2006A>G	p.His669Arg	missense	Exon 11 of 20	ENSP00000356024.3	P20023-3
CR2	ENST00000367058.7	TSL:1	c.1979-229A>G		intron	N/A	ENSP00000356025.3	P20023-1
CR2	ENST00000367059.3	TSL:1	c.1979-229A>G		intron	N/A	ENSP00000356026.3	Q5SR47

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00663

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000426

AC:

107

AN:

251122

AF XY:

0.000449

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000313

AC:

458

AN:

1461590

Hom.:

Cov.:

AF XY:

0.000330

AC XY:

240

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00126

AC:

AN:

33458

American (AMR)

AF:

0.000380

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00440

AC:

115

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000183

AC:

203

AN:

1111800

Other (OTH)

AF:

0.000795

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000335

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41562

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00663

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

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:

0.000484

Hom.:

Bravo

AF:

0.000276

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Immunodeficiency, common variable, 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.93

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.57

M_CAP

Benign

0.018

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.91

PhyloP100

0.76

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.11

Sift

Benign

0.13

Sift4G

Uncertain

0.0080

Polyphen

0.99

Vest4

0.42

MVP

0.75

MPC

0.75

ClinPred

0.061

GERP RS

1.3

gMVP

0.46

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over