rs2274567

chr1-207580276-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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 (★).

• Frequency:
  • Genomes: 𝑓 0.22 (3763 hom., cov: 30)
  • Exomes 𝑓: 0.20 (32684 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.938

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 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]. Clinvar id is 17066.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CR1	NM_000651.6	c.4973A>G	p.His1658Arg	missense_variant	30/47	ENST00000367049.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR1	ENST00000367049.9	c.4973A>G	p.His1658Arg	missense_variant	30/47	5	NM_000651.6	P1
	ENST00000597497.5	n.352+18570T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32706 AN: 151778 Hom.: 3757 Cov.: 30

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

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.: 34 AF XY: 0.206 AC XY: 149760 AN XY: 727084

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.: 30 AF XY: 0.221 AC XY: 16408 AN XY: 74234

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

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Malaria, severe, resistance to Benign:1

protective, no assertion criteria provided

literature only

OMIM

Oct 05, 2010

- -

CR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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	T
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	N
MetaRNN	Benign	0.0016	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs2274567; hg19: chr1-207753621; COSMIC: COSV65458864;