rs2228260

Variant names:

• chr22-28800318-G-A
• rs2228260
• NM_001079539.2: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
• Publications: 10 publications found

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079539.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	NM_001079539.2	MANE Select	c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 6	NP_001073007.1
	XBP1	NM_005080.4		c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 5	NP_005071.2
	XBP1	NM_001393999.1		c.-282C>T		upstream_gene	N/A	NP_001380928.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	ENST00000344347.6	TSL:5 MANE Select	c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 6	ENSP00000343155.5
	XBP1	ENST00000216037.10	TSL:1	c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 5	ENSP00000216037.6
	XBP1	ENST00000933819.1		c.207C>T	p.Pro69Pro	synonymous	Exon 1 of 4	ENSP00000603878.1

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

African (AFR) AF: 0.00387 AC: 116 AN: 29992

American (AMR) AF: 0.0811 AC: 3044 AN: 37536

Ashkenazi Jewish (ASJ) AF: 0.0189 AC: 469 AN: 24760

East Asian (EAS) AF: 0.113 AC: 3988 AN: 35354

South Asian (SAS) AF: 0.0931 AC: 7417 AN: 79656

European-Finnish (FIN) AF: 0.0931 AC: 4491 AN: 48254

Middle Eastern (MID) AF: 0.0129 AC: 70 AN: 5446

European-Non Finnish (NFE) AF: 0.0230 AC: 24879 AN: 1083674

Other (OTH) 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

African (AFR) AF: 0.00585 AC: 243 AN: 41568

American (AMR) AF: 0.0476 AC: 729 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.105 AC: 544 AN: 5164

South Asian (SAS) AF: 0.107 AC: 516 AN: 4834

European-Finnish (FIN) AF: 0.0875 AC: 928 AN: 10610

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0278 AC: 1893 AN: 68006

Other (OTH) AF: 0.0383 AC: 81 AN: 2116

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	10
DANN	Benign	0.95
PhyloP100		-0.42
PromoterAI		-0.021	Neutral
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

Other links and lift over

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