NM_000651.6:c.6830C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000651.6(CR1):c.6830C>G(p.Pro2277Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,613,748 control chromosomes in the GnomAD database, including 34,455 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.19 ( 3009 hom., cov: 30)

Exomes 𝑓: 0.19 ( 31446 hom. )

Consequence

CR1
NM_000651.6 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.827

Publications

42 publications found

Variant links:

Genes affected

CR1 (HGNC:2334): (complement C3b/C4b receptor 1 (Knops blood group)) This gene is a member of the receptors of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The genome is polymorphic at this locus with allele-specific splice variants encoding different isoforms, based on the presence/absence of long homologous repeats (LHRs). The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in this gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus, sarcoidosis and Alzheimer's disease. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum rosetting, conferring protection against severe malaria. [provided by RefSeq, May 2020]

CR1 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=8.209646E-4).

BP6

Variant 1-207616743-C-G is Benign according to our data. Variant chr1-207616743-C-G is described in ClinVar as Benign. ClinVar VariationId is 3059361.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6 link	c.6830C>G	p.Pro2277Arg	missense_variant	Exon 41 of 47	ENST00000367049.9	NP_000642.3	P17927E9PDY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9 link	c.6830C>G	p.Pro2277Arg	missense_variant	Exon 41 of 47	5	NM_000651.6	ENSP00000356016.4		E9PDY4

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28780

AN:

151984

Hom.:

3009

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.251

Gnomad AMR

AF:

0.257

Gnomad ASJ

AF:

0.288

Gnomad EAS

AF:

0.285

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.180

Gnomad MID

AF:

0.223

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.192

GnomAD2 exomes

AF:

0.242

AC:

60224

AN:

249234

AF XY:

0.248

show subpopulations

Gnomad AFR exome

AF:

0.123

Gnomad AMR exome

AF:

0.316

Gnomad ASJ exome

AF:

0.286

Gnomad EAS exome

AF:

0.289

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.189

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

AF:

0.195

AC:

284743

AN:

1461646

Hom.:

31446

Cov.:

AF XY:

0.202

AC XY:

146994

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.127

AC:

4243

AN:

33480

American (AMR)

AF:

0.308

AC:

13796

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

7619

AN:

26136

East Asian (EAS)

AF:

0.250

AC:

9935

AN:

39700

South Asian (SAS)

AF:

0.414

AC:

35697

AN:

86252

European-Finnish (FIN)

AF:

0.179

AC:

9579

AN:

53398

Middle Eastern (MID)

AF:

0.260

AC:

1501

AN:

5768

European-Non Finnish (NFE)

AF:

0.171

AC:

189565

AN:

1111820

Other (OTH)

AF:

0.212

AC:

12808

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

14844

29689

44533

59378

74222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6886

13772

20658

27544

34430

<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:

0.189

AC:

28786

AN:

152102

Hom.:

3009

Cov.:

AF XY:

0.195

AC XY:

14502

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.132

AC:

5488

AN:

41504

American (AMR)

AF:

0.257

AC:

3927

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.288

AC:

999

AN:

3466

East Asian (EAS)

AF:

0.284

AC:

1469

AN:

5178

South Asian (SAS)

AF:

0.430

AC:

2066

AN:

4806

European-Finnish (FIN)

AF:

0.180

AC:

1899

AN:

10568

Middle Eastern (MID)

AF:

0.209

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.180

AC:

12234

AN:

67984

Other (OTH)

AF:

0.197

AC:

415

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1149

2299

3448

4598

5747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.196

Hom.:

994

Bravo

AF:

0.187

TwinsUK

AF:

0.171

AC:

633

ALSPAC

AF:

0.157

AC:

607

ESP6500AA

AF:

0.127

AC:

498

ESP6500EA

AF:

0.182

AC:

1508

ExAC

AF:

0.240

AC:

29024

Asia WGS

AF:

0.409

AC:

1421

AN:

3478

EpiCase

AF:

0.197

EpiControl

AF:

0.205

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CR1-related disorder

Benign:1

Oct 17, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.49

(source)

DANN

Benign

0.28

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.39

.;.;.;T;T

MetaRNN

Benign

0.00082

T;T;T;T;T

MetaSVM

Benign

-0.96

PhyloP100

-0.83

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.76

N;N;N;N;N

REVEL

Benign

0.062

Sift

Benign

0.45

T;T;T;T;T

Sift4G

Benign

0.24

T;T;T;T;T

Polyphen

0.64

.;.;.;.;P

Vest4

0.071

MPC

0.15

ClinPred

0.0016

GERP RS

-5.6

gMVP

0.22

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