rs2228260

Variant names:

• chr22-28800318-G-A
• rs2228260
• ENST00000344347.6:c.207C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28800318-G-A
• chr22-28800318-G-C
• chr22-28800318-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_001079539.2(XBP1):​c.207C>T​(p.Pro69Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,555,012 control chromosomes in the GnomAD database, including 1,709 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.033 (169 hom., cov: 33)
  • Exomes 𝑓: 0.033 (1540 hom.)
• Consequence: XBP1 NM_001079539.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.425

Genes affected

XBP1 (HGNC:12801): (X-box binding protein 1) This gene encodes a transcription factor that regulates MHC class II genes by binding to a promoter element referred to as an X box. This gene product is a bZIP protein, which was also identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. It may increase expression of viral proteins by acting as the DNA binding partner of a viral transactivator. It has been found that upon accumulation of unfolded proteins in the endoplasmic reticulum (ER), the mRNA of this gene is processed to an active form by an unconventional splicing mechanism that is mediated by the endonuclease inositol-requiring enzyme 1 (IRE1). The resulting loss of 26 nt from the spliced mRNA causes a frame-shift and an isoform XBP1(S), which is the functionally active transcription factor. The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. A pseudogene of XBP1 has been identified and localized to chromosome 5. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP7: Synonymous conserved (PhyloP=-0.425 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.207C>T	p.Pro69Pro	synonymous_variant	Exon 1 of 6		NP_001073007.1
XBP1	NM_005080.4	c.207C>T	p.Pro69Pro	synonymous_variant	Exon 1 of 5		NP_005071.2
XBP1	NM_001393999.1	c.-282C>T		upstream_gene_variant			NP_001380928.1
XBP1	NM_001394000.1	c.-282C>T		upstream_gene_variant			NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.207C>T	p.Pro69Pro	synonymous_variant	Exon 1 of 6	5		ENSP00000343155.5

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 4999 AN: 152168 Hom.: 167 Cov.: 33

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0278

Gnomad OTH AF: 0.0344

GnomAD2 exomes AF: 0.0584 AC: 8813 AN: 150948 AF XY: 0.0578

Gnomad AFR exome AF: 0.00518

Gnomad AMR exome AF: 0.0881

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.0902

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0332 AC: 46521 AN: 1402732 Hom.: 1540 Cov.: 31 AF XY: 0.0352 AC XY: 24392 AN XY: 693584

Gnomad4 AFR exome AF: 0.00387 AC: 116 AN: 29992

Gnomad4 AMR exome AF: 0.0811 AC: 3044 AN: 37536

Gnomad4 ASJ exome AF: 0.0189 AC: 469 AN: 24760

Gnomad4 EAS exome AF: 0.113 AC: 3988 AN: 35354

Gnomad4 SAS exome AF: 0.0931 AC: 7417 AN: 79656

Gnomad4 FIN exome AF: 0.0931 AC: 4491 AN: 48254

Gnomad4 NFE exome AF: 0.0230 AC: 24879 AN: 1083674

Gnomad4 Remaining exome AF: 0.0353 AC: 2047 AN: 58060

GnomAD4 genome AF: 0.0329 AC: 5010 AN: 152280 Hom.: 169 Cov.: 33 AF XY: 0.0374 AC XY: 2783 AN XY: 74456

Gnomad4 AFR AF: 0.00585 AC: 0.00584584 AN: 0.00584584

Gnomad4 AMR AF: 0.0476 AC: 0.0476284 AN: 0.0476284

Gnomad4 ASJ AF: 0.0135 AC: 0.0135369 AN: 0.0135369

Gnomad4 EAS AF: 0.105 AC: 0.105345 AN: 0.105345

Gnomad4 SAS AF: 0.107 AC: 0.106744 AN: 0.106744

Gnomad4 FIN AF: 0.0875 AC: 0.0874647 AN: 0.0874647

Gnomad4 NFE AF: 0.0278 AC: 0.0278358 AN: 0.0278358

Gnomad4 OTH AF: 0.0383 AC: 0.0382798 AN: 0.0382798

Alfa AF: 0.0254 Hom.: 33

Bravo AF: 0.0259

Asia WGS AF: 0.101 AC: 351 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228260; hg19: chr22-29196306; COSMIC: COSV53276792; COSMIC: COSV53276792;