chr1-207523952-C-T

Variant names:

• chr1-207523952-C-T
• rs199777103
• NM_000651.6:c.829C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000651.6(CR1):​c.829C>T​(p.Arg277Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000442 in 1,611,732 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R277H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.161
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15464833).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000651.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR1	NM_000651.6	MANE Select	c.829C>T	p.Arg277Cys	missense	Exon 5 of 47	NP_000642.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR1	ENST00000367049.9	TSL:5 MANE Select	c.829C>T	p.Arg277Cys	missense	Exon 5 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.829C>T	p.Arg277Cys	missense	Exon 5 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367050.8	TSL:1	n.950C>T		non_coding_transcript_exon	Exon 5 of 13

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000252 AC: 62 AN: 245680 AF XY: 0.000254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000442

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000457 AC: 667 AN: 1459506 Hom.: 1 Cov.: 34 AF XY: 0.000441 AC XY: 320 AN XY: 726038

African (AFR) AF: 0.0000599 AC: 2 AN: 33404

American (AMR) AF: 0.000492 AC: 22 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86164

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.000549 AC: 610 AN: 1111684

Other (OTH) AF: 0.000415 AC: 25 AN: 60182

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74430

African (AFR) AF: 0.000193 AC: 8 AN: 41480

American (AMR) AF: 0.000654 AC: 10 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000264

ExAC AF: 0.000225 AC: 27

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.96
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.85	T
PhyloP100		-0.16
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.20
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.74	P
Vest4		0.29
MVP		0.51
MPC		3.5
ClinPred		0.035	T
GERP RS		-1.4
gMVP		0.62
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs199777103; hg19: chr1-207697297; COSMIC: COSV65458350;