rs746473308

Variant names:

• chr1-207563899-C-T
• rs746473308
• NM_000651.6:c.3622C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000651.6(CR1):​c.3622C>T​(p.Arg1208Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000058 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000040 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.390
• Publications: 0 publications found

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]

CR1-AS1 (HGNC:40160):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.081359535).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000651.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR1	NM_000651.6	MANE Select	c.3622C>T	p.Arg1208Cys	missense	Exon 22 of 47	NP_000642.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR1	ENST00000367049.9	TSL:5 MANE Select	c.3622C>T	p.Arg1208Cys	missense	Exon 22 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.2272C>T	p.Arg758Cys	missense	Exon 14 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.2272C>T	p.Arg758Cys	missense	Exon 14 of 39	ENSP00000356018.1	P17927

Frequencies

GnomAD3 genomes AF: 0.0000576 AC: 6 AN: 104084 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000331

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000589 AC: 12 AN: 203832 AF XY: 0.0000360

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000559

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000398 AC: 55 AN: 1382772 Hom.: 5 Cov.: 30 AF XY: 0.0000392 AC XY: 27 AN XY: 688602

African (AFR) AF: 0.00 AC: 0 AN: 17084

American (AMR) AF: 0.0000493 AC: 2 AN: 40596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24384

East Asian (EAS) AF: 0.00 AC: 0 AN: 38140

South Asian (SAS) AF: 0.00 AC: 0 AN: 76712

European-Finnish (FIN) AF: 0.000577 AC: 30 AN: 52016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4214

European-Non Finnish (NFE) AF: 0.0000177 AC: 19 AN: 1073224

Other (OTH) AF: 0.0000709 AC: 4 AN: 56402

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000576 AC: 6 AN: 104102 Hom.: 0 Cov.: 15 AF XY: 0.0000599 AC XY: 3 AN XY: 50082

African (AFR) AF: 0.00 AC: 0 AN: 12142

American (AMR) AF: 0.00 AC: 0 AN: 10760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2890

East Asian (EAS) AF: 0.00 AC: 0 AN: 4154

South Asian (SAS) AF: 0.00 AC: 0 AN: 2818

European-Finnish (FIN) AF: 0.000473 AC: 4 AN: 8460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.0000331 AC: 2 AN: 60338

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000849 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	KNOPS BLOOD GROUP SYSTEM;C1970028:Malaria, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	1.0
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.78	T
PhyloP100		0.39
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.084
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.15
MutPred		0.48		Loss of disorder (P = 0.1105)
MVP		0.76
MPC		2.8
ClinPred		0.34	T
GERP RS		-0.30
gMVP		0.25
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs746473308; hg19: chr1-207737244; COSMIC: COSV65455847; COSMIC: COSV65455847;