chr1-207580276-A-G

Variant names:

• chr1-207580276-A-G
• rs2274567
• NM_000651.6:c.4973A>G

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.4973A>G​(p.His1658Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,613,500 control chromosomes in the GnomAD database, including 36,447 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.22 (3763 hom., cov: 30)
  • Exomes 𝑓: 0.20 (32684 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign; protective no assertion criteria provided B:2
• Conservation: PhyloP100: 0.938
• Publications: 70 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016205907).
• BP6: Variant 1-207580276-A-G is Benign according to our data. Variant chr1-207580276-A-G is described in ClinVar as Benign|protective. ClinVar VariationId is 17066.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 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.4973A>G	p.His1658Arg	missense	Exon 30 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.4973A>G	p.His1658Arg	missense	Exon 30 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.3623A>G	p.His1208Arg	missense	Exon 22 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.3623A>G	p.His1208Arg	missense	Exon 22 of 39	ENSP00000356018.1	P17927

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32706 AN: 151778 Hom.: 3757 Cov.: 30

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.265

Gnomad ASJ AF: 0.290

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.250 AC: 62373 AN: 249098 AF XY: 0.256

Gnomad AFR exome AF: 0.216

Gnomad AMR exome AF: 0.321

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.199 AC: 290604 AN: 1461604 Hom.: 32684 Cov.: 34 AF XY: 0.206 AC XY: 149760 AN XY: 727084

African (AFR) AF: 0.217 AC: 7279 AN: 33476

American (AMR) AF: 0.314 AC: 14033 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 7651 AN: 26130

East Asian (EAS) AF: 0.253 AC: 10039 AN: 39698

South Asian (SAS) AF: 0.420 AC: 36212 AN: 86252

European-Finnish (FIN) AF: 0.180 AC: 9632 AN: 53400

Middle Eastern (MID) AF: 0.268 AC: 1542 AN: 5764

European-Non Finnish (NFE) AF: 0.172 AC: 190910 AN: 1111804

Other (OTH) AF: 0.220 AC: 13306 AN: 60366

GnomAD4 genome AF: 0.215 AC: 32728 AN: 151896 Hom.: 3763 Cov.: 30 AF XY: 0.221 AC XY: 16408 AN XY: 74234

African (AFR) AF: 0.219 AC: 9088 AN: 41424

American (AMR) AF: 0.266 AC: 4057 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.290 AC: 1005 AN: 3466

East Asian (EAS) AF: 0.288 AC: 1480 AN: 5142

South Asian (SAS) AF: 0.438 AC: 2100 AN: 4800

European-Finnish (FIN) AF: 0.181 AC: 1914 AN: 10568

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.181 AC: 12326 AN: 67930

Other (OTH) AF: 0.220 AC: 463 AN: 2100

Alfa AF: 0.204 Hom.: 2249

Bravo AF: 0.217

TwinsUK AF: 0.172 AC: 636

ALSPAC AF: 0.159 AC: 611

ESP6500AA AF: 0.223 AC: 875

ESP6500EA AF: 0.183 AC: 1524

ExAC AF: 0.251 AC: 30304

Asia WGS AF: 0.431 AC: 1497 AN: 3478

EpiCase AF: 0.198

EpiControl AF: 0.207

ClinVar

ClinVar submissions

Significance: Benign; protective

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CR1-related disorder (1)
-	-	-	Malaria, severe, resistance to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.4
DANN	Benign	0.27
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.94
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.14
Sift	Benign	0.90	T
Sift4G	Benign	0.26	T
Polyphen		0.15	B
Vest4		0.074
MPC		0.55
ClinPred		0.021	T
GERP RS		0.18
gMVP		0.63
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: rs2274567; hg19: chr1-207753621; COSMIC: COSV65458864;