1-207526921-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000651.6(CR1):c.1055C>G(p.Thr352Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (3 hom., cov: 17)
  • Exomes 𝑓: 0.000053 (18 hom.)
  • Failed GnomAD Quality Control
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031938016).
• BP6: Variant 1-207526921-C-G is Benign according to our data. Variant chr1-207526921-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2394007.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 4 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR1	NM_000651.6	c.1055C>G	p.Thr352Arg	missense_variant	6/47	ENST00000367049.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR1	ENST00000367049.9	c.1055C>G	p.Thr352Arg	missense_variant	6/47	5	NM_000651.6	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 45 AN: 113470 Hom.: 3 Cov.: 17 FAILED QC

Gnomad AFR AF: 0.00211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000876

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: 0.0000165

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 13 AN: 96378 Hom.: 4 AF XY: 0.0000793 AC XY: 4 AN XY: 50432

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000527 AC: 71 AN: 1348200 Hom.: 18 Cov.: 30 AF XY: 0.0000373 AC XY: 25 AN XY: 669420

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.0000570

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: 0.00000475

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000396 AC: 45 AN: 113520 Hom.: 3 Cov.: 17 AF XY: 0.000497 AC XY: 27 AN XY: 54360

Gnomad4 AFR AF: 0.00210

Gnomad4 AMR AF: 0.0000876

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000165

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

ExAC AF: 0.0000996 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.28
Dann	Benign	0.19
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0043	N
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.032	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.49	N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.57	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;.;B
Vest4		0.11
MVP		0.40
MPC		2.0
ClinPred		0.0022	T
GERP RS		-7.5
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs751182802; hg19: chr1-207700266;