rs75282758

Variant names:

• chr1-207468605-C-T
• rs75282758
• NM_001006658.3:c.524C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-207468605-C-T
• chr1-207468605-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001006658.3(CR2):​c.524C>T​(p.Pro175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,614,062 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P175S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (47 hom.)
• Consequence: CR2 NM_001006658.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 0.530
• Publications: 13 publications found

Genes affected

CR2 (HGNC:2336): (complement C3d receptor 2) This gene encodes a membrane protein, which functions as a receptor for Epstein-Barr virus (EBV) binding on B and T lymphocytes. Genetic variations in this gene are associated with susceptibility to systemic lupus erythematosus type 9 (SLEB9). Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

CR2 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• common variable immunodeficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020729423).
• BP6: Variant 1-207468605-C-T is Benign according to our data. Variant chr1-207468605-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 402563.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00359 (547/152290) while in subpopulation SAS AF = 0.00727 (35/4816). AF 95% confidence interval is 0.00555. There are 1 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 47 Unknown,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006658.3. 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
	CR2	NM_001006658.3	MANE Select	c.524C>T	p.Pro175Leu	missense	Exon 3 of 20	NP_001006659.1	P20023-3
	CR2	NM_001877.5		c.524C>T	p.Pro175Leu	missense	Exon 3 of 19	NP_001868.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	ENST00000367057.8	TSL:1 MANE Select	c.524C>T	p.Pro175Leu	missense	Exon 3 of 20	ENSP00000356024.3	P20023-3
	CR2	ENST00000367058.7	TSL:1	c.524C>T	p.Pro175Leu	missense	Exon 3 of 19	ENSP00000356025.3	P20023-1
	CR2	ENST00000367059.3	TSL:1	c.524C>T	p.Pro175Leu	missense	Exon 3 of 18	ENSP00000356026.3	Q5SR47

Frequencies

GnomAD3 genomes AF: 0.00359 AC: 546 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00705

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00603

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00432 AC: 1086 AN: 251348 AF XY: 0.00465

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00641

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00645 AC: 9431 AN: 1461772 Hom.: 47 Cov.: 33 AF XY: 0.00649 AC XY: 4718 AN XY: 727186

African (AFR) AF: 0.00102 AC: 34 AN: 33466

American (AMR) AF: 0.00103 AC: 46 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00394 AC: 103 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00802 AC: 692 AN: 86258

European-Finnish (FIN) AF: 0.000618 AC: 33 AN: 53418

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.00737 AC: 8191 AN: 1111942

Other (OTH) AF: 0.00480 AC: 290 AN: 60394

GnomAD4 genome AF: 0.00359 AC: 547 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74460

African (AFR) AF: 0.00140 AC: 58 AN: 41558

American (AMR) AF: 0.00196 AC: 30 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00727 AC: 35 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00516 Hom.: 14

Bravo AF: 0.00379

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00448 AC: 544

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	1	1	not specified (2)
-	-	1	CR2-related disorder (1)
-	-	1	Immunodeficiency, common variable, 7 (1)
-	1	-	Systemic lupus erythematosus, susceptibility to, 9;C3542922:Immunodeficiency, common variable, 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.53
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.67
Sift	Benign	0.31	T
Sift4G	Benign	0.38	T
Polyphen		0.89	P
Vest4		0.39
MVP		0.81
MPC		0.52
ClinPred		0.033	T
GERP RS		4.9
Varity_R		0.072
gMVP		0.59
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs75282758; hg19: chr1-207641950; COSMIC: COSV99056561; COSMIC: COSV99056561;