1-207506725-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000651.6(CR1):c.313C>T(p.Arg105Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00902 in 1,613,150 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (86 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.31

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064602196).
• BP6: Variant 1-207506725-C-T is Benign according to our data. Variant chr1-207506725-C-T is described in ClinVar as [Benign]. Clinvar id is 3024765.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 9 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR1	NM_000651.6	c.313C>T	p.Arg105Cys	missense_variant	3/47	ENST00000367049.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR1	ENST00000367049.9	c.313C>T	p.Arg105Cys	missense_variant	3/47	5	NM_000651.6	P1

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1123 AN: 152140 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00738 AC: 1836 AN: 248936 Hom.: 11 AF XY: 0.00746 AC XY: 1008 AN XY: 135058

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00349

Gnomad ASJ exome AF: 0.00686

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00745

GnomAD4 exome AF: 0.00919 AC: 13432 AN: 1460892 Hom.: 86 Cov.: 30 AF XY: 0.00890 AC XY: 6470 AN XY: 726740

Gnomad4 AFR exome AF: 0.000897

Gnomad4 AMR exome AF: 0.00334

Gnomad4 ASJ exome AF: 0.00544

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00288

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0105

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.00738 AC: 1123 AN: 152258 Hom.: 9 Cov.: 32 AF XY: 0.00743 AC XY: 553 AN XY: 74452

Gnomad4 AFR AF: 0.00178

Gnomad4 AMR AF: 0.00504

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0127

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.0160 Hom.: 93

Bravo AF: 0.00622

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.00318 AC: 12

ESP6500EA AF: 0.0103 AC: 85

ExAC AF: 0.00759 AC: 917

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0107

EpiControl AF: 0.00937

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

CR1: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	12
Dann	Benign	0.72
Eigen	Benign	-0.88
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0052	N
MetaRNN	Benign	0.0065	T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.043	D;D;D;D;T
Sift4G	Uncertain	0.030	D;D;D;D;D
Polyphen		0.99, 1.0	.;.;.;D;D
Vest4		0.20
MVP		0.62
MPC		0.45
ClinPred		0.046	T
GERP RS		-7.7
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs11587944; hg19: chr1-207680070; COSMIC: COSV65458943;