NM_000651.6:c.6031G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000651.6(CR1):c.6031G>A(p.Val2011Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,613,970 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.021 ( 63 hom., cov: 32)

Exomes 𝑓: 0.026 ( 663 hom. )

Consequence

CR1
NM_000651.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0330

Publications

24 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008785188).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3227/152270) while in subpopulation NFE AF = 0.0285 (1940/68010). AF 95% confidence interval is 0.0275. There are 63 homozygotes in GnomAd4. There are 1629 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 63 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000651.6. 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
	CR1	NM_000651.6	MANE Select	c.6031G>A	p.Val2011Met	missense	Exon 37 of 47	NP_000642.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CR1	ENST00000367049.9	TSL:5 MANE Select	c.6031G>A	p.Val2011Met	missense	Exon 37 of 47	ENSP00000356016.4
CR1	ENST00000400960.7	TSL:1	c.4681G>A	p.Val1561Met	missense	Exon 29 of 39	ENSP00000383744.2
CR1	ENST00000367051.6	TSL:5	c.4681G>A	p.Val1561Met	missense	Exon 29 of 39	ENSP00000356018.1

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3226

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00502

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.0271

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.0529

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0285

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.0260

AC:

6489

AN:

249234

AF XY:

0.0247

show subpopulations

Gnomad AFR exome

AF:

0.00491

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.000890

Gnomad FIN exome

AF:

0.0532

Gnomad NFE exome

AF:

0.0278

Gnomad OTH exome

AF:

0.0248

GnomAD4 exome

AF:

0.0262

AC:

38300

AN:

1461700

Hom.:

663

Cov.:

AF XY:

0.0255

AC XY:

18508

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.00299

AC:

100

AN:

33480

American (AMR)

AF:

0.0469

AC:

2098

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00708

AC:

185

AN:

26136

East Asian (EAS)

AF:

0.000705

AC:

AN:

39700

South Asian (SAS)

AF:

0.00755

AC:

651

AN:

86258

European-Finnish (FIN)

AF:

0.0560

AC:

2990

AN:

53402

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0279

AC:

31024

AN:

1111862

Other (OTH)

AF:

0.0199

AC:

1201

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2172

4344

6515

8687

10859

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1144

2288

3432

4576

5720

<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:

0.0212

AC:

3227

AN:

152270

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1629

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00500

AC:

208

AN:

41572

American (AMR)

AF:

0.0271

AC:

414

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.00155

AC:

AN:

5176

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0529

AC:

561

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0285

AC:

1940

AN:

68010

Other (OTH)

AF:

0.0199

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

169

338

507

676

845

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0248

Hom.:

125

Bravo

AF:

0.0192

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0265

AC:

102

ESP6500AA

AF:

0.00597

AC:

ESP6500EA

AF:

0.0256

AC:

214

ExAC

AF:

0.0248

AC:

3005

EpiCase

AF:

0.0261

EpiControl

AF:

0.0229

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.47

CADD

Benign

5.3

(source)

DANN

Benign

0.95

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0088

MetaSVM

Benign

-0.97

PhyloP100

0.033

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.47

REVEL

Benign

0.15

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0050

Polyphen

0.77

Vest4

0.047

MPC

0.16

ClinPred

0.0068

GERP RS

0.74

gMVP

0.43

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over