rs2274567

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000651.6(CR1):c.4973A>G(p.His1658Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,500 control chromosomes in the GnomAD database, including 36,447 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,protective (no stars).

Frequency

Genomes: 𝑓 0.22 ( 3763 hom., cov: 30)

Exomes 𝑓: 0.20 ( 32684 hom. )

Consequence

CR1
NM_000651.6 missense

Scores

Clinical Significance

Benign; protective no assertion criteria provided B:2

Conservation

PhyloP100: 0.938

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:

ENSG00000236911 (HGNC:40160):

ENSG00000236911 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016205907).

BP6

Variant 1-207580276-A-G is Benign according to our data. Variant chr1-207580276-A-G is described in ClinVar as [Benign, protective]. Clinvar id is 17066.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6 link	c.4973A>G	p.His1658Arg	missense_variant	Exon 30 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.4973A>G	p.His1658Arg	missense_variant	Exon 30 of 47	5	NM_000651.6	ENSP00000356016.4		E9PDY4

Frequencies

GnomAD3 genomes

AF:

0.215

AC:

32706

AN:

151778

Hom.:

3757

Cov.:

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.252

Gnomad AMR

AF:

0.265

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.289

Gnomad SAS

AF:

0.439

Gnomad FIN

AF:

0.181

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.181

Gnomad OTH

AF:

0.214

GnomAD3 exomes

AF:

0.250

AC:

62373

AN:

249098

Hom.:

8951

AF XY:

0.256

AC XY:

34538

AN XY:

135122

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.321

Gnomad ASJ exome

AF:

0.288

Gnomad EAS exome

AF:

0.292

Gnomad SAS exome

AF:

0.424

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.191

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.199

AC:

290604

AN:

1461604

Hom.:

32684

Cov.:

AF XY:

0.206

AC XY:

149760

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.314

Gnomad4 ASJ exome

AF:

0.293

Gnomad4 EAS exome

AF:

0.253

Gnomad4 SAS exome

AF:

0.420

Gnomad4 FIN exome

AF:

0.180

Gnomad4 NFE exome

AF:

0.172

Gnomad4 OTH exome

AF:

0.220

GnomAD4 genome

AF:

0.215

AC:

32728

AN:

151896

Hom.:

3763

Cov.:

AF XY:

0.221

AC XY:

16408

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.266

Gnomad4 ASJ

AF:

0.290

Gnomad4 EAS

AF:

0.288

Gnomad4 SAS

AF:

0.438

Gnomad4 FIN

AF:

0.181

Gnomad4 NFE

AF:

0.181

Gnomad4 OTH

AF:

0.220

Alfa

AF:

0.200

Hom.:

1595

Bravo

AF:

0.217

TwinsUK

AF:

0.172

AC:

636

ALSPAC

AF:

0.159

AC:

611

ESP6500AA

AF:

0.223

AC:

875

ESP6500EA

AF:

0.183

AC:

1524

ExAC

AF:

0.251

AC:

30304

Asia WGS

AF:

0.431

AC:

1497

AN:

3478

EpiCase

AF:

0.198

EpiControl

AF:

0.207

ClinVar

Significance: Benign; protective

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Malaria, severe, resistance to

Benign:1

Oct 05, 2010

OMIM

Significance: protective

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

0.13

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

8.4

DANN

Benign

0.27

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.45

.;.;.;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.4

N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.90

T;T;T;T;T

Sift4G

Benign

0.26

T;T;T;T;T

Polyphen

0.15, 0.99

.;.;.;B;D

Vest4

0.074

MPC

0.55

ClinPred

0.021

GERP RS

0.18

gMVP

0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over