rs6691117

Variant names:

• chr1-207609586-A-G
• rs6691117
• NM_000651.6:c.6193A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-207609586-A-G
• chr1-207609586-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000651.6(CR1):​c.6193A>G​(p.Ile2065Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,612,446 control chromosomes in the GnomAD database, including 69,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (16803 hom., cov: 31)
  • Exomes 𝑓: 0.24 (52693 hom.)
• Consequence: CR1 NM_000651.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.96
• Publications: 77 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.2969766E-6).
• BP6: Variant 1-207609586-A-G is Benign according to our data. Variant chr1-207609586-A-G is described in ClinVar as Benign. ClinVar VariationId is 1252113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR1	NM_000651.6	c.6193A>G	p.Ile2065Val	missense_variant	Exon 37 of 47	ENST00000367049.9	NP_000642.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR1	ENST00000367049.9	c.6193A>G	p.Ile2065Val	missense_variant	Exon 37 of 47	5	NM_000651.6	ENSP00000356016.4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60820 AN: 151966 Hom.: 16765 Cov.: 31

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.318

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.241

Gnomad MID AF: 0.280

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.321 AC: 79225 AN: 246530 AF XY: 0.315

Gnomad AFR exome AF: 0.797

Gnomad AMR exome AF: 0.408

Gnomad ASJ exome AF: 0.321

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.271

GnomAD4 exome AF: 0.243 AC: 355524 AN: 1460362 Hom.: 52693 Cov.: 37 AF XY: 0.248 AC XY: 179804 AN XY: 726362

African (AFR) AF: 0.803 AC: 26869 AN: 33454

American (AMR) AF: 0.402 AC: 17877 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8384 AN: 26086

East Asian (EAS) AF: 0.267 AC: 10585 AN: 39660

South Asian (SAS) AF: 0.428 AC: 36850 AN: 86102

European-Finnish (FIN) AF: 0.244 AC: 13009 AN: 53332

Middle Eastern (MID) AF: 0.310 AC: 1790 AN: 5768

European-Non Finnish (NFE) AF: 0.201 AC: 223183 AN: 1111166

Other (OTH) AF: 0.281 AC: 16977 AN: 60344

GnomAD4 genome AF: 0.401 AC: 60914 AN: 152084 Hom.: 16803 Cov.: 31 AF XY: 0.402 AC XY: 29871 AN XY: 74350

African (AFR) AF: 0.783 AC: 32446 AN: 41456

American (AMR) AF: 0.362 AC: 5536 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.318 AC: 1103 AN: 3472

East Asian (EAS) AF: 0.306 AC: 1582 AN: 5176

South Asian (SAS) AF: 0.445 AC: 2142 AN: 4814

European-Finnish (FIN) AF: 0.241 AC: 2557 AN: 10596

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.213 AC: 14471 AN: 67980

Other (OTH) AF: 0.358 AC: 754 AN: 2108

Alfa AF: 0.286 Hom.: 32181

Bravo AF: 0.422

TwinsUK AF: 0.199 AC: 737

ALSPAC AF: 0.186 AC: 716

ESP6500AA AF: 0.751 AC: 2892

ESP6500EA AF: 0.213 AC: 1761

ExAC AF: 0.327 AC: 39530

Asia WGS AF: 0.483 AC: 1677 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 24, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23856853, 31182772, 21700265, 24018213, 23591632) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CR1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	5.1
DANN	Benign	0.11
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00037	N
LIST_S2	Benign	0.37	.;.;.;T;T
MetaRNN	Benign	0.0000063	T;T;T;T;T
MetaSVM	Benign	-0.96	T
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.60	N;N;N;N;N
REVEL	Benign	0.090
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0, 0.0010	.;.;.;B;B
Vest4		0.0090
MPC		0.092
ClinPred		0.0012	T
GERP RS		2.5
gMVP		0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs6691117; hg19: chr1-207782931; COSMIC: COSV65458244; COSMIC: COSV65458244;