1-207474297-G-A

Variant names:

• chr1-207474297-G-A
• rs398122863
• NM_001006658.3:c.2297G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001006658.3(CR2):​c.2297G>A​(p.Trp766*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CR2 NM_001006658.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.19
• Publications: 2 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-207474297-G-A is Pathogenic according to our data. Variant chr1-207474297-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 35453.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2297G>A	p.Trp766*	stop_gained	Exon 13 of 20	NP_001006659.1
	CR2	NM_001877.5		c.2120G>A	p.Trp707*	stop_gained	Exon 12 of 19	NP_001868.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	ENST00000367057.8	TSL:1 MANE Select	c.2297G>A	p.Trp766*	stop_gained	Exon 13 of 20	ENSP00000356024.3
	CR2	ENST00000367058.7	TSL:1	c.2120G>A	p.Trp707*	stop_gained	Exon 12 of 19	ENSP00000356025.3
	CR2	ENST00000367059.3	TSL:1	c.2120G>A	p.Trp707*	stop_gained	Exon 12 of 18	ENSP00000356026.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency, common variable, 7 Pathogenic:1

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		4.2
Vest4		0.88
GERP RS		5.7
Mutation Taster		=10/190	disease causing (ClinVar)

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: rs398122863; hg19: chr1-207647642;