rs3737002

Positions:

• chr1-207587428-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000651.6(CR1):​c.5573C>T​(p.Thr1858Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,346 control chromosomes in the GnomAD database, including 64,072 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1858A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4928 hom., cov: 33)
  • Exomes 𝑓: 0.28 (59144 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.587

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]

ENSG00000236911 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00201419).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR1	NM_000651.6	c.5573C>T	p.Thr1858Met	missense_variant	34/47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.5573C>T	p.Thr1858Met	missense_variant	34/47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34978 AN: 152024 Hom.: 4922 Cov.: 33

Gnomad AFR AF: 0.0754

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.241

GnomAD3 exomes AF: 0.282 AC: 70327 AN: 248984 Hom.: 10548 AF XY: 0.283 AC XY: 38225 AN XY: 135078

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.330

Gnomad SAS exome AF: 0.312

Gnomad FIN exome AF: 0.327

Gnomad NFE exome AF: 0.268

Gnomad OTH exome AF: 0.276

GnomAD4 exome AF: 0.280 AC: 409370 AN: 1461204 Hom.: 59144 Cov.: 34 AF XY: 0.281 AC XY: 204001 AN XY: 726916

Gnomad4 AFR exome AF: 0.0672

Gnomad4 AMR exome AF: 0.354

Gnomad4 ASJ exome AF: 0.236

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.307

Gnomad4 FIN exome AF: 0.321

Gnomad4 NFE exome AF: 0.279

Gnomad4 OTH exome AF: 0.263

GnomAD4 genome AF: 0.230 AC: 34990 AN: 152142 Hom.: 4928 Cov.: 33 AF XY: 0.237 AC XY: 17614 AN XY: 74370

Gnomad4 AFR AF: 0.0754

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.245

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.324

Gnomad4 NFE AF: 0.275

Gnomad4 OTH AF: 0.239

Alfa AF: 0.261 Hom.: 10039

Bravo AF: 0.224

TwinsUK AF: 0.293 AC: 1087

ALSPAC AF: 0.281 AC: 1082

ESP6500AA AF: 0.0748 AC: 272

ESP6500EA AF: 0.276 AC: 2253

ExAC AF: 0.275 AC: 33182

Asia WGS AF: 0.262 AC: 912 AN: 3478

EpiCase AF: 0.267

EpiControl AF: 0.265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.2
DANN	Uncertain	0.99
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.0090	N
LIST_S2	Benign	0.40	.;.;.;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.85	N;N;N;N;N
REVEL	Benign	0.092
Sift	Uncertain	0.019	D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		0.99, 1.0	.;.;.;D;D
Vest4		0.13
MPC		0.52
ClinPred		0.012	T
GERP RS		-0.082
gMVP		0.46

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: rs3737002; hg19: chr1-207760773; COSMIC: COSV65458238;