rs2296160

Positions:

• chr1-207621975-A-G
• chr1-207621975-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000651.6(CR1):​c.7255A>G​(p.Thr2419Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,593,392 control chromosomes in the GnomAD database, including 532,780 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.81 (50485 hom., cov: 31)
  • Exomes 𝑓: 0.82 (482295 hom.)
• Consequence: CR1 NM_000651.6 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.00

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6148501E-6).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR1	NM_000651.6	c.7255A>G	p.Thr2419Ala	missense_variant, splice_region_variant	44/47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.7255A>G	p.Thr2419Ala	missense_variant, splice_region_variant	44/47	5	NM_000651.6	ENSP00000356016	P1

Frequencies

GnomAD3 genomes AF: 0.813 AC: 123577 AN: 151992 Hom.: 50449 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.901

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.807

Gnomad OTH AF: 0.834

GnomAD3 exomes AF: 0.819 AC: 187609 AN: 228938 Hom.: 77449 AF XY: 0.820 AC XY: 101209 AN XY: 123444

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.907

Gnomad ASJ exome AF: 0.811

Gnomad EAS exome AF: 0.654

Gnomad SAS exome AF: 0.902

Gnomad FIN exome AF: 0.803

Gnomad NFE exome AF: 0.803

Gnomad OTH exome AF: 0.816

GnomAD4 exome AF: 0.817 AC: 1177041 AN: 1441282 Hom.: 482295 Cov.: 32 AF XY: 0.818 AC XY: 585561 AN XY: 715600

Gnomad4 AFR exome AF: 0.812

Gnomad4 AMR exome AF: 0.902

Gnomad4 ASJ exome AF: 0.813

Gnomad4 EAS exome AF: 0.638

Gnomad4 SAS exome AF: 0.898

Gnomad4 FIN exome AF: 0.804

Gnomad4 NFE exome AF: 0.814

Gnomad4 OTH exome AF: 0.815

GnomAD4 genome AF: 0.813 AC: 123666 AN: 152110 Hom.: 50485 Cov.: 31 AF XY: 0.815 AC XY: 60604 AN XY: 74374

Gnomad4 AFR AF: 0.814

Gnomad4 AMR AF: 0.860

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.657

Gnomad4 SAS AF: 0.902

Gnomad4 FIN AF: 0.809

Gnomad4 NFE AF: 0.807

Gnomad4 OTH AF: 0.834

Alfa AF: 0.804 Hom.: 25911

Bravo AF: 0.815

TwinsUK AF: 0.818 AC: 3034

ALSPAC AF: 0.821 AC: 3164

ESP6500AA AF: 0.817 AC: 3108

ESP6500EA AF: 0.817 AC: 6750

ExAC AF: 0.808 AC: 97310

Asia WGS AF: 0.807 AC: 2806 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.0040
DANN	Benign	0.16
Eigen	Benign	-2.9
Eigen_PC	Benign	-3.0
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.19	.;.;.;T;T
MetaRNN	Benign	0.0000016	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.0	N;N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.99	T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.0	.;.;.;.;B
Vest4		0.020
MPC		0.11
ClinPred		0.0025	T
GERP RS		-8.3
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs2296160; hg19: chr1-207795320; COSMIC: COSV65461428;