rs17047661

Positions:

• chr1-207609544-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000651.6(CR1):​c.6151A>G​(p.Arg2051Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0339 in 1,613,794 control chromosomes in the GnomAD database, including 14,885 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.18 (7751 hom., cov: 32)
  • Exomes 𝑓: 0.019 (7134 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.459

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7961715E-5).
• BP6: Variant 1-207609544-A-G is Benign according to our data. Variant chr1-207609544-A-G is described in ClinVar as [Benign]. Clinvar id is 3056679.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR1	NM_000651.6	c.6151A>G	p.Arg2051Gly	missense_variant	37/47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.6151A>G	p.Arg2051Gly	missense_variant	37/47	5	NM_000651.6	ENSP00000356016	P1

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26575 AN: 152084 Hom.: 7725 Cov.: 32

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0690

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00332

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.0460 AC: 11454 AN: 248756 Hom.: 3128 AF XY: 0.0351 AC XY: 4737 AN XY: 134986

Gnomad AFR exome AF: 0.629

Gnomad AMR exome AF: 0.0320

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.0210

GnomAD4 exome AF: 0.0192 AC: 28135 AN: 1461592 Hom.: 7134 Cov.: 31 AF XY: 0.0168 AC XY: 12238 AN XY: 727078

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.0356

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.0435

GnomAD4 genome AF: 0.175 AC: 26650 AN: 152202 Hom.: 7751 Cov.: 32 AF XY: 0.169 AC XY: 12613 AN XY: 74430

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.0688

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00332

Gnomad4 OTH AF: 0.129

Alfa AF: 0.0381 Hom.: 2979

Bravo AF: 0.200

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.571 AC: 2160

ESP6500EA AF: 0.00328 AC: 27

ExAC AF: 0.0549 AC: 6630

Asia WGS AF: 0.0410 AC: 143 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00415

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 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	0.24
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	4.4
DANN	Benign	0.88
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.27	.;.;.;T;T
MetaRNN	Benign	0.000018	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.3	N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.37	T;T;T;T;T
Sift4G	Benign	0.093	T;T;T;T;T
Polyphen		0.26, 0.99	.;.;.;B;D
Vest4		0.082
MPC		0.30
ClinPred		0.022	T
GERP RS		-2.0
gMVP		0.80

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: rs17047661; hg19: chr1-207782889; COSMIC: COSV65459478; COSMIC: COSV65459478;