rs4844609

chr1-207609571-A-Gchr1-207609571-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000651.6(CR1):c.6178A>G(p.Thr2060Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/18 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: not found (cov: 31)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.871

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10322967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR1	NM_000651.6	c.6178A>G	p.Thr2060Ala	missense_variant	37/47	ENST00000367049.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR1	ENST00000367049.9	c.6178A>G	p.Thr2060Ala	missense_variant	37/47	5	NM_000651.6	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	3.3
Dann	Benign	0.29
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0078	N
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.89	N;N;N;N;N
REVEL	Benign	0.064
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.60	T;T;T;T;T
Polyphen		0.0, 0.065	.;.;.;B;B
Vest4		0.025
MutPred		0.55		.;.;.;.;Loss of stability (P = 0.081);
MVP		0.22
MPC		0.12
ClinPred		0.031	T
GERP RS		2.5
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs4844609; hg19: chr1-207782916;