rs17047660

Positions:

• chr1-207609511-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.6118A>G​(p.Lys2040Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0132 in 1,613,850 control chromosomes in the GnomAD database, including 2,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.068 (1158 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (1050 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.526

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=0.017027318).
• BP6: Variant 1-207609511-A-G is Benign according to our data. Variant chr1-207609511-A-G is described in ClinVar as [Benign]. Clinvar id is 3056450.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR1	NM_000651.6	c.6118A>G	p.Lys2040Glu	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.6118A>G	p.Lys2040Glu	missense_variant	37/47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.0674 AC: 10257 AN: 152094 Hom.: 1153 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0182 AC: 4520 AN: 248948 Hom.: 473 AF XY: 0.0136 AC XY: 1834 AN XY: 135086

Gnomad AFR exome AF: 0.245

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000360

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.00877

GnomAD4 exome AF: 0.00756 AC: 11057 AN: 1461638 Hom.: 1050 Cov.: 31 AF XY: 0.00662 AC XY: 4816 AN XY: 727104

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.0137

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000742

Gnomad4 OTH exome AF: 0.0177

GnomAD4 genome AF: 0.0676 AC: 10282 AN: 152212 Hom.: 1158 Cov.: 32 AF XY: 0.0655 AC XY: 4875 AN XY: 74430

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.0289

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0124 Hom.: 372

Bravo AF: 0.0772

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.220 AC: 832

ESP6500EA AF: 0.00182 AC: 15

ExAC AF: 0.0214 AC: 2579

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00125

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 26, 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	0.20
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.97
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.54	.;.;.;T;T
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.065	T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.0050, 0.96	.;.;.;B;D
Vest4		0.053
MPC		0.31
ClinPred		0.0044	T
GERP RS		1.4
gMVP		0.47

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: rs17047660; hg19: chr1-207782856; COSMIC: COSV65460344; COSMIC: COSV65460344;