chr1-207564032-C-G

Variant names:

• chr1-207564032-C-G
• rs745791931
• NM_000651.6:c.3755C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_000651.6(CR1):​c.3755C>G​(p.Thr1252Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,395,910 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 0.0000036 (1 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.71
• Publications: 0 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]

CR1-AS1 (HGNC:40160):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07111293).
• BP6: Variant 1-207564032-C-G is Benign according to our data. Variant chr1-207564032-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3496753.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3755C>G	p.Thr1252Arg	missense	Exon 22 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.3755C>G	p.Thr1252Arg	missense	Exon 22 of 47	ENSP00000356016.4	E9PDY4
	CR1	ENST00000400960.7	TSL:1	c.2405C>G	p.Thr802Arg	missense	Exon 14 of 39	ENSP00000383744.2	P17927
	CR1	ENST00000367051.6	TSL:5	c.2405C>G	p.Thr802Arg	missense	Exon 14 of 39	ENSP00000356018.1	P17927

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD2 exomes AF: 0.0000232 AC: 4 AN: 172442 AF XY: 0.0000215

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000241

Gnomad OTH exome AF: 0.000463

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1395910 Hom.: 1 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 695006

African (AFR) AF: 0.00 AC: 0 AN: 19654

American (AMR) AF: 0.00 AC: 0 AN: 39286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24286

East Asian (EAS) AF: 0.00 AC: 0 AN: 38826

South Asian (SAS) AF: 0.00 AC: 0 AN: 77138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4950

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1082314

Other (OTH) AF: 0.0000350 AC: 2 AN: 57176

GnomAD4 genome Cov.: 18

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000263 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

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	Benign	0.042
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.050
DANN	Benign	0.17
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.013	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.1	T
PhyloP100		-2.7
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.23	N
REVEL	Benign	0.056
Sift	Benign	0.66	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.47		Loss of phosphorylation at T1252 (P = 0.0483)
MVP		0.41
MPC		2.0
ClinPred		0.012	T
GERP RS		-6.2
gMVP		0.61
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745791931; hg19: chr1-207737377;