1-207473553-T-C

Variant names:

• chr1-207473553-T-C
• rs4308977
• NM_001006658.3:c.1987T>C

Variant summary

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

The NM_001006658.3(CR2):​c.1987T>C​(p.Ser663Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,609,678 control chromosomes in the GnomAD database, including 80,499 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (9346 hom., cov: 32)
  • Exomes 𝑓: 0.31 (71153 hom.)
• Consequence: CR2 NM_001006658.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.33
• Publications: 36 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7824769E-4).
• BP6: Variant 1-207473553-T-C is Benign according to our data. Variant chr1-207473553-T-C is described in ClinVar as Benign. ClinVar VariationId is 402560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	NM_001006658.3	MANE Select	c.1987T>C	p.Ser663Pro	missense	Exon 11 of 20	NP_001006659.1
	CR2	NM_001877.5		c.1979-248T>C		intron	N/A	NP_001868.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	ENST00000367057.8	TSL:1 MANE Select	c.1987T>C	p.Ser663Pro	missense	Exon 11 of 20	ENSP00000356024.3
	CR2	ENST00000367058.7	TSL:1	c.1979-248T>C		intron	N/A	ENSP00000356025.3
	CR2	ENST00000367059.3	TSL:1	c.1979-248T>C		intron	N/A	ENSP00000356026.3

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50782 AN: 151954 Hom.: 9317 Cov.: 32

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.270 AC: 67724 AN: 250936 AF XY: 0.269

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.284

Gnomad EAS exome AF: 0.112

Gnomad FIN exome AF: 0.230

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.282

GnomAD4 exome AF: 0.305 AC: 444806 AN: 1457606 Hom.: 71153 Cov.: 39 AF XY: 0.303 AC XY: 219532 AN XY: 725296

African (AFR) AF: 0.498 AC: 16624 AN: 33368

American (AMR) AF: 0.179 AC: 7994 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 7483 AN: 26114

East Asian (EAS) AF: 0.121 AC: 4822 AN: 39688

South Asian (SAS) AF: 0.235 AC: 20230 AN: 86178

European-Finnish (FIN) AF: 0.228 AC: 12167 AN: 53398

Middle Eastern (MID) AF: 0.323 AC: 1857 AN: 5750

European-Non Finnish (NFE) AF: 0.321 AC: 355635 AN: 1108160

Other (OTH) AF: 0.299 AC: 17994 AN: 60256

GnomAD4 genome AF: 0.334 AC: 50863 AN: 152072 Hom.: 9346 Cov.: 32 AF XY: 0.327 AC XY: 24289 AN XY: 74348

African (AFR) AF: 0.490 AC: 20340 AN: 41478

American (AMR) AF: 0.237 AC: 3618 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3470

East Asian (EAS) AF: 0.108 AC: 558 AN: 5178

South Asian (SAS) AF: 0.230 AC: 1108 AN: 4820

European-Finnish (FIN) AF: 0.226 AC: 2390 AN: 10588

Middle Eastern (MID) AF: 0.307 AC: 89 AN: 290

European-Non Finnish (NFE) AF: 0.308 AC: 20942 AN: 67964

Other (OTH) AF: 0.315 AC: 665 AN: 2110

Alfa AF: 0.316 Hom.: 26868

Bravo AF: 0.342

TwinsUK AF: 0.319 AC: 1181

ALSPAC AF: 0.326 AC: 1256

ESP6500AA AF: 0.497 AC: 2188

ESP6500EA AF: 0.316 AC: 2716

ExAC AF: 0.281 AC: 34078

Asia WGS AF: 0.193 AC: 669 AN: 3478

EpiCase AF: 0.303

EpiControl AF: 0.308

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency, common variable, 7 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.29
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00081	N
LIST_S2	Benign	0.050	T
MetaRNN	Benign	0.00018	T
MetaSVM	Benign	-0.91	T
PhyloP100		-1.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.076
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.069
MPC		0.21
ClinPred		0.0019	T
GERP RS		1.2
gMVP		0.52
Mutation Taster		=98/2	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: rs4308977; hg19: chr1-207646898; COSMIC: COSV65506623; COSMIC: COSV65506623;