rs367798627

Variant names:

• chr5-147831630-G-A
• rs367798627
• NM_001379610.1:c.-53C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-147831630-G-A
• chr5-147831630-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001379610.1(SPINK1):​c.-53C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000176 in 1,608,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SPINK1 NM_001379610.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.23
• Publications: 6 publications found

Genes affected

SPINK1 (HGNC:11244): (serine peptidase inhibitor Kazal type 1) The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis. [provided by RefSeq, Oct 2008]

SPINK1 Gene-Disease associations (from GenCC):

• hereditary chronic pancreatitis

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• tropical pancreatitis

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

LOC124901101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000184 (28/152292) while in subpopulation AMR AF = 0.000523 (8/15298). AF 95% confidence interval is 0.00026. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 28 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.-53C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	ENST00000296695.10	NP_001366539.1
SPINK1	NM_001379610.1	c.-53C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.-53C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 4	1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000296695.10	c.-53C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000510027.2	c.-53C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 3	3		ENSP00000427376.1
SPINK1	ENST00000510027.2	c.-53C>T		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000427376.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1456080 Hom.: 0 Cov.: 30 AF XY: 0.000164 AC XY: 119 AN XY: 724354

African (AFR) AF: 0.0000602 AC: 2 AN: 33220

American (AMR) AF: 0.000180 AC: 8 AN: 44444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39292

South Asian (SAS) AF: 0.0000933 AC: 8 AN: 85714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51612

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.000200 AC: 222 AN: 1109844

Other (OTH) AF: 0.000216 AC: 13 AN: 60152

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.000523 AC: 8 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000200

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:3

Jun 25, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-53C>T variant is located in the 5' untranslated region (5’ UTR) of the SPINK1 gene. This variant results from a C to T substitution 53 bases upstream from the first translated codon. This nucleotide position is conserved through primates. The variant has been detected in multiple individuals with pancreatitis (Witt H et al. Nat. Genet., 2000 Jun;25:213-6; Boulling A et al. Eur. J. Hum. Genet., 2011 Oct;19:1066-73; Rosendahl J et al. Gut, 2013 Apr;62:582-92; Palermo JJ et al. Pancreas, 2016 10;45:1347-52). Functional studies showed that this alteration reduces the SPINK1 promoter activity (Boulling A et al. Eur. J. Hum. Genet., 2011 Oct;19:1066-73; Derikx MH et al. Am. J. Physiol. Gastrointest. Liver Physiol., 2015 May;308:G779-84). Another study showed that the variant may reduce protein expression, rather than mRNA expression, by creating upstream open reading frame (Calvo SE et al. Proc. Natl. Acad. Sci. U.S.A., 2009 May;106:7507-12). However, it is unknown whether the reduced expression is sufficient to cause disease. In addition, the variant has been detected in multiple unaffected individuals at our laboratory. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant occurs in a non-coding region of the SPINK1 gene. It does not change the encoded amino acid sequence of the SPINK1 protein. This variant is present in population databases (rs367798627, gnomAD 0.1%). This variant has been observed in individual(s) with chronic pancreatitis (PMID: 10835640, 21610753, 22427236, 27171515). ClinVar contains an entry for this variant (Variation ID: 565669). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SPINK1 function (PMID: 21610753). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary pancreatitis;C1842402:Tropical pancreatitis Uncertain:1

Jun 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 20, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SPINK1 c.-53C>T variant (rs367798627) is reported in individuals with pancreatitis (Boulling 2011, Derikx 2015, Palermo 2016, Rosendahl 2013, Witt 2000), and is reported in ClinVar (Variation ID: 565669). Functional studies demonstrate reduced protein expression (Calvo 2009) or reduced promoter activity (Boulling 2011, Derikx 2015), but it's unknown whether the reduction is sufficient to cause disease. This variant is only found on five alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant is located in the 5' untranslated region and creates a novel protein translation start codon that if utilized may cause a frameshift. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Boulling A et al. Assessing the pathological relevance of SPINK1 promoter variants. Eur J Hum Genet. 2011 Oct;19(10):1066-73. PMID: 21610753. Calvo SE et al. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7507-12. PMID: 19372376. Derikx MH et al. Functional significance of SPINK1 promoter variants in chronic pancreatitis. Am J Physiol Gastrointest Liver Physiol. 2015 May 1;308(9):G779-84. PMID: 25792561. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. PMID: 27171515. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92. PMID: 22427236. Witt H et al. Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet. 2000 Jun;25(2):213-6. PMID: 10835640. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.50
PhyloP100		1.2
PromoterAI		-0.094	Neutral
Mutation Taster		=57/243	disease causing (ClinVar)

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: rs367798627; hg19: chr5-147211193;