rs139230275

Variant names:

• chr1-207473572-A-G
• rs139230275
• NM_001006658.3:c.2006A>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.2006A>G​(p.His669Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,613,894 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H669H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: CR2 NM_001006658.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.755

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.030501753).
• BP6: Variant 1-207473572-A-G is Benign according to our data. Variant chr1-207473572-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540322.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000313 (458/1461590) while in subpopulation MID AF = 0.00226 (13/5762). AF 95% confidence interval is 0.00133. There are 4 homozygotes in GnomAdExome4. There are 240 alleles in the male GnomAdExome4 subpopulation. Median coverage is 41. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CR2	NM_001006658.3	c.2006A>G	p.His669Arg	missense_variant	Exon 11 of 20	ENST00000367057.8	NP_001006659.1
CR2	NM_001877.5	c.1979-229A>G		intron_variant	Intron 10 of 18		NP_001868.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CR2	ENST00000367057.8	c.2006A>G	p.His669Arg	missense_variant	Exon 11 of 20	1	NM_001006658.3	ENSP00000356024.3

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000426 AC: 107 AN: 251122 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00447

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000313 AC: 458 AN: 1461590 Hom.: 4 Cov.: 41 AF XY: 0.000330 AC XY: 240 AN XY: 727098

Gnomad4 AFR exome AF: 0.00126 AC: 42 AN: 33458

Gnomad4 AMR exome AF: 0.000380 AC: 17 AN: 44702

Gnomad4 ASJ exome AF: 0.00440 AC: 115 AN: 26128

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39694

Gnomad4 SAS exome AF: 0.000232 AC: 20 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.000183 AC: 203 AN: 1111800

Gnomad4 Remaining exome AF: 0.000795 AC: 48 AN: 60368

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74474

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240604 AN: 0.0000240604

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00663 AC: 0.00662824 AN: 0.00662824

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000621 AC: 0.000620861 AN: 0.000620861

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000338 AC: 0.000338106 AN: 0.000338106

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000484 Hom.: 0

Bravo AF: 0.000276

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 17, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CR2 c.2006A>G; p.His669Arg variant (rs139230275) is reported in the literature in at least one individual affected with inflammatory bowel disease from exome sequencing, but it is unclear what other variants are present in this individual (Kelsen 2015). This variant is reported in ClinVar (Variation ID: 540322), and is found in the Ashkenazi Jewish population with an allele frequency of 0.44% (46/10366 alleles) in the Genome Aggregation Database. The histidine at codon 669 is highly conserved, and computational analyses (SIFT: tolerated, PolyPhen-2: possibly damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the p.His669Arg variant is uncertain at this time. References: Kelsen JR et al. Exome sequencing analysis reveals variants in primary immunodeficiency genes in patients with very early onset inflammatory bowel disease. Gastroenterology. 2015 Nov;149(6):1415-24. -

Immunodeficiency, common variable, 7 Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Benign	0.93
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.42
MVP		0.75
MPC		0.75
ClinPred		0.061	T
GERP RS		1.3
gMVP		0.46
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139230275; hg19: chr1-207646917;