1-207565887-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000651.6(CR1):​c.3916G>A​(p.Glu1306Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,610,904 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

CR1
NM_000651.6 missense

Scores

17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.944
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.07716316).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CR1NM_000651.6 linkc.3916G>A p.Glu1306Lys missense_variant Exon 24 of 47 ENST00000367049.9 NP_000642.3 P17927E9PDY4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CR1ENST00000367049.9 linkc.3916G>A p.Glu1306Lys missense_variant Exon 24 of 47 5 NM_000651.6 ENSP00000356016.4 E9PDY4

Frequencies

GnomAD3 genomes
AF:
0.0000666
AC:
10
AN:
150230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000967
GnomAD3 exomes
AF:
0.0000482
AC:
12
AN:
248908
Hom.:
0
AF XY:
0.0000592
AC XY:
8
AN XY:
135084
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000128
AC:
187
AN:
1460674
Hom.:
1
Cov.:
33
AF XY:
0.000131
AC XY:
95
AN XY:
726678
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000153
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.0000666
AC:
10
AN:
150230
Hom.:
0
Cov.:
32
AF XY:
0.0000273
AC XY:
2
AN XY:
73384
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000967
Alfa
AF:
0.0000330
Hom.:
0
Bravo
AF:
0.0000604
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000243
AC:
2
ExAC
AF:
0.0000580
AC:
7
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2566G>A (p.E856K) alteration is located in exon 16 (coding exon 16) of the CR1 gene. This alteration results from a G to A substitution at nucleotide position 2566, causing the glutamic acid (E) at amino acid position 856 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
5.6
DANN
Benign
0.94
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.0048
N
LIST_S2
Benign
0.26
.;.;.;T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.077
T;T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.76
N;N;N;N
REVEL
Benign
0.16
Sift
Benign
0.49
T;T;T;T
Sift4G
Benign
0.43
T;T;T;T
Polyphen
0.63
.;.;.;P
Vest4
0.12
MVP
0.53
MPC
0.14
ClinPred
0.039
T
GERP RS
-5.0
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.15
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200885342; hg19: chr1-207739232; COSMIC: COSV65464556; COSMIC: COSV65464556; API