1-207472818-C-T

Position:

• chr1-207472818-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000640301.1(CR2):​c.67C>T​(p.Arg23Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,613,944 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R23L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (45 hom., cov: 32)
  • Exomes 𝑓: 0.014 (208 hom.)
• Consequence: CR2 ENST00000640301.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.97

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019263625).
• BP6: Variant 1-207472818-C-T is Benign according to our data. Variant chr1-207472818-C-T is described in ClinVar as [Benign]. Clinvar id is 473095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-207472818-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0209 (3189/152252) while in subpopulation AFR AF= 0.032 (1329/41534). AF 95% confidence interval is 0.0306. There are 45 homozygotes in gnomad4. There are 1512 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CR2	NM_001006658.3	c.1617C>T	p.Thr539=	synonymous_variant	10/20	ENST00000367057.8
CR2	NM_001877.5	c.1617C>T	p.Thr539=	synonymous_variant	10/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CR2	ENST00000367057.8	c.1617C>T	p.Thr539=	synonymous_variant	10/20	1	NM_001006658.3	P1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3190 AN: 152134 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0363

GnomAD3 exomes AF: 0.0151 AC: 3806 AN: 251298 Hom.: 38 AF XY: 0.0150 AC XY: 2032 AN XY: 135812

Gnomad AFR exome AF: 0.0340

Gnomad AMR exome AF: 0.0140

Gnomad ASJ exome AF: 0.0211

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.0169

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0143 AC: 20902 AN: 1461692 Hom.: 208 Cov.: 31 AF XY: 0.0142 AC XY: 10350 AN XY: 727146

Gnomad4 AFR exome AF: 0.0339

Gnomad4 AMR exome AF: 0.0148

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00552

Gnomad4 FIN exome AF: 0.0154

Gnomad4 NFE exome AF: 0.0145

Gnomad4 OTH exome AF: 0.0160

GnomAD4 genome AF: 0.0209 AC: 3189 AN: 152252 Hom.: 45 Cov.: 32 AF XY: 0.0203 AC XY: 1512 AN XY: 74458

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.0202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0162

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.0359

Alfa AF: 0.0146 Hom.: 19

Bravo AF: 0.0219

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.0166 AC: 143

ExAC AF: 0.0153 AC: 1854

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0187

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Immunodeficiency, common variable, 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.58
DANN	Benign	0.85
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;N
GERP RS		-5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34349246; hg19: chr1-207646163;