1-207563993-G-A

Position:

• chr1-207563993-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000651.6(CR1):​c.3716G>A​(p.Arg1239His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00089 in 1,522,900 control chromosomes in the GnomAD database, including 155 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 0.00077 (5 hom., cov: 18)
  • Exomes 𝑓: 0.00090 (150 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.291

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0656406).
• BS2: High Homozygotes in GnomAd4 at 5 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CR1	NM_000651.6	c.3716G>A	p.Arg1239His	missense_variant	22/47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.3716G>A	p.Arg1239His	missense_variant	22/47	5	NM_000651.6	ENSP00000356016	P1
	ENST00000597497.5	n.353-11013C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 93 AN: 120936 Hom.: 5 Cov.: 18

Gnomad AFR AF: 0.000272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00146

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: 0.00104

Gnomad OTH AF: 0.000562

GnomAD3 exomes AF: 0.000534 AC: 122 AN: 228592 Hom.: 18 AF XY: 0.000564 AC XY: 70 AN XY: 124144

Gnomad AFR exome AF: 0.000214

Gnomad AMR exome AF: 0.000286

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000584

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000984

Gnomad OTH exome AF: 0.000521

GnomAD4 exome AF: 0.000901 AC: 1263 AN: 1401914 Hom.: 150 Cov.: 32 AF XY: 0.000842 AC XY: 588 AN XY: 698056

Gnomad4 AFR exome AF: 0.000683

Gnomad4 AMR exome AF: 0.000437

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000258

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000769 AC: 93 AN: 120986 Hom.: 5 Cov.: 18 AF XY: 0.000766 AC XY: 45 AN XY: 58732

Gnomad4 AFR AF: 0.000271

Gnomad4 AMR AF: 0.00145

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00105

Gnomad4 OTH AF: 0.000558

Alfa AF: 0.000476 Hom.: 1

ESP6500AA AF: 0.000377 AC: 1

ESP6500EA AF: 0.00111 AC: 9

ExAC AF: 0.000480 AC: 55

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

The c.2366G>A (p.R789H) alteration is located in exon 14 (coding exon 14) of the CR1 gene. This alteration results from a G to A substitution at nucleotide position 2366, causing the arginine (R) at amino acid position 789 to be replaced by a histidine (H). 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	0.092
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.5
DANN	Benign	0.81
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.14	.;.;.;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.066	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.54	N;N;N;N
REVEL	Benign	0.043
Sift	Benign	0.34	T;T;T;T
Sift4G	Benign	0.67	T;T;T;T
Polyphen		0.53	.;.;.;P
Vest4		0.063
MVP		0.35
MPC		2.1
ClinPred		0.0018	T
GERP RS		-2.7
gMVP		0.30

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: rs201018148; hg19: chr1-207737338; COSMIC: COSV65464029; COSMIC: COSV65464029;