rs112859639

Variant names:

• chr1-207485454-TTC-T
• rs112859639
• NM_001006658.3:c.3189-8_3189-7delCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001006658.3(CR2):​c.3189-8_3189-7delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000753 in 1,544,162 control chromosomes in the GnomAD database, including 13 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (6 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (7 hom.)
• Consequence: CR2 NM_001006658.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0420
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 1-207485454-TTC-T is Benign according to our data. Variant chr1-207485454-TTC-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00375 (571/152358) while in subpopulation AFR AF = 0.0128 (533/41588). AF 95% confidence interval is 0.0119. There are 6 homozygotes in GnomAd4. There are 285 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 Unknown,AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	NM_001006658.3	MANE Select	c.3189-8_3189-7delCT		splice_region intron	N/A	NP_001006659.1
	CR2	NM_001877.5		c.3012-8_3012-7delCT		splice_region intron	N/A	NP_001868.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CR2	ENST00000367057.8	TSL:1 MANE Select	c.3189-9_3189-8delTC		splice_region intron	N/A	ENSP00000356024.3
	CR2	ENST00000367058.7	TSL:1	c.3012-9_3012-8delTC		splice_region intron	N/A	ENSP00000356025.3
	CR2	ENST00000367059.3	TSL:1	c.2826-9_2826-8delTC		splice_region intron	N/A	ENSP00000356026.3

Frequencies

GnomAD3 genomes AF: 0.00369 AC: 562 AN: 152240 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00101 AC: 254 AN: 250492 AF XY: 0.000664

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000425 AC: 591 AN: 1391804 Hom.: 7 AF XY: 0.000360 AC XY: 251 AN XY: 696572

African (AFR) AF: 0.0131 AC: 419 AN: 32050

American (AMR) AF: 0.00114 AC: 51 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00269 AC: 15 AN: 5586

European-Non Finnish (NFE) AF: 0.0000267 AC: 28 AN: 1048402

Other (OTH) AF: 0.00133 AC: 77 AN: 58048

GnomAD4 genome AF: 0.00375 AC: 571 AN: 152358 Hom.: 6 Cov.: 31 AF XY: 0.00383 AC XY: 285 AN XY: 74502

African (AFR) AF: 0.0128 AC: 533 AN: 41588

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68038

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00185 Hom.: 1

Bravo AF: 0.00423

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Immunodeficiency, common variable, 7 (2)
-	-	1	CR2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.042
Mutation Taster		=100/0	polymorphism

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: rs112859639; hg19: chr1-207658799;