1-207454458-G-C

Position:

• chr1-207454458-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001006658.3(CR2):​c.40G>C​(p.Val14Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,427,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V14V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CR2 NM_001006658.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.54

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030532628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3	c.40G>C	p.Val14Leu	missense_variant	1/20	ENST00000367057.8
CR2	NM_001877.5	c.40G>C	p.Val14Leu	missense_variant	1/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8	c.40G>C	p.Val14Leu	missense_variant	1/20	1	NM_001006658.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1427238 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 708710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000831 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, common variable, 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2019

This sequence change replaces valine with leucine at codon 14 of the CR2 protein (p.Val14Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs754824683, ExAC 0.01%). This variant has not been reported in the literature in individuals with CR2-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.058
DANN	Benign	0.70
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.6
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.60	T;T;T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.46	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.013
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.046
MutPred		0.50		Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);Loss of sheet (P = 0.0037);
MVP		0.067
MPC		0.16
ClinPred		0.061	T
GERP RS		-8.5
Varity_R		0.042
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs754824683; hg19: chr1-207627803;