rs41274768

Variant names:

• chr1-207609424-G-A
• rs41274768
• NM_000651.6:c.6031G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000651.6(CR1):​c.6031G>A​(p.Val2011Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,613,970 control chromosomes in the GnomAD database, including 726 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (63 hom., cov: 32)
  • Exomes 𝑓: 0.026 (663 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 24 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008785188).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3227/152270) while in subpopulation NFE AF = 0.0285 (1940/68010). AF 95% confidence interval is 0.0275. There are 63 homozygotes in GnomAd4. There are 1629 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.6031G>A	p.Val2011Met	missense_variant	Exon 37 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.6031G>A	p.Val2011Met	missense_variant	Exon 37 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3226 AN: 152152 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0260 AC: 6489 AN: 249234 AF XY: 0.0247

Gnomad AFR exome AF: 0.00491

Gnomad AMR exome AF: 0.0480

Gnomad ASJ exome AF: 0.00855

Gnomad EAS exome AF: 0.000890

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0262 AC: 38300 AN: 1461700 Hom.: 663 Cov.: 31 AF XY: 0.0255 AC XY: 18508 AN XY: 727134

African (AFR) AF: 0.00299 AC: 100 AN: 33480

American (AMR) AF: 0.0469 AC: 2098 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00708 AC: 185 AN: 26136

East Asian (EAS) AF: 0.000705 AC: 28 AN: 39700

South Asian (SAS) AF: 0.00755 AC: 651 AN: 86258

European-Finnish (FIN) AF: 0.0560 AC: 2990 AN: 53402

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0279 AC: 31024 AN: 1111862

Other (OTH) AF: 0.0199 AC: 1201 AN: 60374

GnomAD4 genome AF: 0.0212 AC: 3227 AN: 152270 Hom.: 63 Cov.: 32 AF XY: 0.0219 AC XY: 1629 AN XY: 74464

African (AFR) AF: 0.00500 AC: 208 AN: 41572

American (AMR) AF: 0.0271 AC: 414 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5176

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4830

European-Finnish (FIN) AF: 0.0529 AC: 561 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1940 AN: 68010

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0248 Hom.: 125

Bravo AF: 0.0192

TwinsUK AF: 0.0248 AC: 92

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.00597 AC: 24

ESP6500EA AF: 0.0256 AC: 214

ExAC AF: 0.0248 AC: 3005

EpiCase AF: 0.0261

EpiControl AF: 0.0229

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.3
DANN	Benign	0.95
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.62	.;.;.;T;T
MetaRNN	Benign	0.0088	T;T;T;T;T
MetaSVM	Benign	-0.97	T
PhyloP100		0.033
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.47	N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		0.77, 0.43	.;.;.;P;B
Vest4		0.047
MPC		0.16
ClinPred		0.0068	T
GERP RS		0.74
gMVP		0.43
Mutation Taster		=99/1	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: rs41274768; hg19: chr1-207782769;