1-207565858-C-G

Variant names:

• chr1-207565858-C-G
• rs199990810
• NM_000651.6:c.3887C>G

Variant summary

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

The NM_000651.6(CR1):​c.3887C>G​(p.Ser1296Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S1296F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.3887C>G	p.Ser1296Cys	missense_variant	Exon 24 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.3887C>G	p.Ser1296Cys	missense_variant	Exon 24 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248860 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.85e-7 AC: 1 AN: 1460642 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000829 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	19
DANN	Uncertain	0.99
Eigen	Uncertain	0.20
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.81	.;.;.;T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-0.42	T
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.8	D;D;D;N
REVEL	Benign	0.29
Sift	Uncertain	0.016	D;D;D;T
Sift4G	Benign	0.062	T;T;T;T
Polyphen		1.0	.;.;.;D
Vest4		0.47
MutPred		0.60		.;.;.;Loss of disorder (P = 0.0276);
MVP		0.84
MPC		0.49
ClinPred		0.96	D
GERP RS		2.7
gMVP		0.34

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: rs199990810; hg19: chr1-207739203;