NM_000651.6:c.3964C>T

Variant names:

• chr1-207567835-C-T
• rs771362085
• NM_000651.6:c.3964C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000651.6(CR1):​c.3964C>T​(p.Pro1322Ser) 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. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1322T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.153

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]

ENSG00000236911 (HGNC:40160):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33674568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.3964C>T	p.Pro1322Ser	missense_variant	Exon 25 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.3964C>T	p.Pro1322Ser	missense_variant	Exon 25 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	-0.044
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.58	.;.;.;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.40	T
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.13	T;T;T;T
Sift4G	Benign	0.090	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.29
MutPred		0.55		.;.;.;Loss of catalytic residue at P1322 (P = 0.0532);
MVP		0.77
MPC		0.44
ClinPred		0.83	D
GERP RS		2.7
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs771362085; hg19: chr1-207741180;