rs3811381

Variant names:

• chr1-207616743-C-G
• rs3811381
• NM_000651.6:c.6830C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-207616743-C-G
• chr1-207616743-C-A
• chr1-207616743-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (3009 hom., cov: 30)
  • Exomes 𝑓: 0.19 (31446 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.827
• Publications: 42 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]

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3059361.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

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.6830C>G	p.Pro2277Arg	missense	Exon 41 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.6830C>G	p.Pro2277Arg	missense	Exon 41 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.5480C>G	p.Pro1827Arg	missense	Exon 33 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.5480C>G	p.Pro1827Arg	missense	Exon 33 of 39	ENSP00000356018.1	P17927

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

GnomAD2 exomes AF: 0.242 AC: 60224 AN: 249234 AF XY: 0.248

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 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

African (AFR) AF: 0.127 AC: 4243 AN: 33480

American (AMR) AF: 0.308 AC: 13796 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7619 AN: 26136

East Asian (EAS) AF: 0.250 AC: 9935 AN: 39700

South Asian (SAS) AF: 0.414 AC: 35697 AN: 86252

European-Finnish (FIN) AF: 0.179 AC: 9579 AN: 53398

Middle Eastern (MID) AF: 0.260 AC: 1501 AN: 5768

European-Non Finnish (NFE) AF: 0.171 AC: 189565 AN: 1111820

Other (OTH) AF: 0.212 AC: 12808 AN: 60368

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

African (AFR) AF: 0.132 AC: 5488 AN: 41504

American (AMR) AF: 0.257 AC: 3927 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 999 AN: 3466

East Asian (EAS) AF: 0.284 AC: 1469 AN: 5178

South Asian (SAS) AF: 0.430 AC: 2066 AN: 4806

European-Finnish (FIN) AF: 0.180 AC: 1899 AN: 10568

Middle Eastern (MID) AF: 0.209 AC: 61 AN: 292

European-Non Finnish (NFE) AF: 0.180 AC: 12234 AN: 67984

Other (OTH) AF: 0.197 AC: 415 AN: 2108

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CR1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.00082	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.83
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.062
Sift	Benign	0.45	T
Sift4G	Benign	0.24	T
Polyphen		0.64	P
Vest4		0.071
MPC		0.15
ClinPred		0.0016	T
GERP RS		-5.6
gMVP		0.22
Mutation Taster		=100/0	polymorphism (auto)

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