1-207616743-C-G

Position:

• chr1-207616743-C-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.6830C>G​(p.Pro2277Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 1,613,748 control chromosomes in the GnomAD database, including 34,455 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 (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3009 hom., cov: 30)
  • Exomes 𝑓: 0.19 (31446 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.827

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.209646E-4).
• BP6: Variant 1-207616743-C-G is Benign according to our data. Variant chr1-207616743-C-G is described in ClinVar as [Benign]. Clinvar id is 3059361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR1	NM_000651.6	c.6830C>G	p.Pro2277Arg	missense_variant	41/47	ENST00000367049.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR1	ENST00000367049.9	c.6830C>G	p.Pro2277Arg	missense_variant	41/47	5	NM_000651.6	P1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28780 AN: 151984 Hom.: 3009 Cov.: 30

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.288

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.223

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.192

GnomAD3 exomes AF: 0.242 AC: 60224 AN: 249234 Hom.: 8484 AF XY: 0.248 AC XY: 33581 AN XY: 135210

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.289

Gnomad SAS exome AF: 0.418

Gnomad FIN exome AF: 0.178

Gnomad NFE exome AF: 0.189

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.195 AC: 284743 AN: 1461646 Hom.: 31446 Cov.: 33 AF XY: 0.202 AC XY: 146994 AN XY: 727104

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.308

Gnomad4 ASJ exome AF: 0.292

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.414

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.189 AC: 28786 AN: 152102 Hom.: 3009 Cov.: 30 AF XY: 0.195 AC XY: 14502 AN XY: 74378

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.257

Gnomad4 ASJ AF: 0.288

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.430

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.197

Alfa AF: 0.196 Hom.: 994

Bravo AF: 0.187

TwinsUK AF: 0.171 AC: 633

ALSPAC AF: 0.157 AC: 607

ESP6500AA AF: 0.127 AC: 498

ESP6500EA AF: 0.182 AC: 1508

ExAC AF: 0.240 AC: 29024

Asia WGS AF: 0.409 AC: 1421 AN: 3478

EpiCase AF: 0.197

EpiControl AF: 0.205

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	0.087
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.49
DANN	Benign	0.28
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.39	.;.;.;T;T
MetaRNN	Benign	0.00082	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.76	N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.45	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.64	.;.;.;.;P
Vest4		0.071
MPC		0.15
ClinPred		0.0016	T
GERP RS		-5.6
gMVP		0.22

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: rs3811381; hg19: chr1-207790088; COSMIC: COSV65458249;