rs367798627

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC124901101 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.-53C>T		5_prime_UTR_premature_start_codon_gain_variant	1/4	ENST00000296695.10	NP_001366539.1
SPINK1	NM_001379610.1	c.-53C>T		5_prime_UTR_variant	1/4	ENST00000296695.10	NP_001366539.1

Ensembl

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

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000933

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000200

Gnomad4 OTH exome AF: 0.000216

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	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 protein 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 14, 2024

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 20, 2022

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

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: rs367798627; hg19: chr5-147211193;