5-147831719-A-G

Variant names:

• chr5-147831719-A-G
• rs755968566
• NM_001354966.2:c.-142T>C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003122.5(SPINK1):​c.-142T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,516,408 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 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SPINK1 NM_003122.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.42

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=-0.58).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000158 (24/152334) while in subpopulation NFE AF= 0.000279 (19/68034). AF 95% confidence interval is 0.000182. There are 0 homozygotes in gnomad4. There are 7 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 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.-142T>C		upstream_gene_variant		ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.-142T>C		upstream_gene_variant		1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000510027.2	c.-142T>C		upstream_gene_variant		3		ENSP00000427376.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 252 AN: 1364074 Hom.: 0 Cov.: 30 AF XY: 0.000185 AC XY: 124 AN XY: 671976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000322

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000779

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000159

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74490

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000234

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

Dec 11, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with pancreatitis (PMID: 17003641, 21610753). ClinVar contains an entry for this variant (Variation ID: 239502). Experimental studies have shown that this non-coding change disrupts SPINK1 protein function (PMID: 21610753, 28556356, 25792561). -

Jun 25, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-142T>C variant is located in the 5' untranslated region (5’ UTR) of the SPINK1 gene. This variant results from a T to C substitution 142 bases upstream from the first translated codon. This nucleotide position is well conserved in available vertebrate species. The variant has been detected in multiple individuals with pancreatitis (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Boulling A et al. Eur. J. Hum. Genet., 2011 Oct;19:1066-73). Functional studies showed that this alteration disrupts a putative HNF1-binding site and 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). However, it is unknown whether the reduced promoter activity 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. -

Tropical pancreatitis Uncertain:1

Nov 29, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis;C1842402:Tropical pancreatitis Uncertain:1

May 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 24, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SPINK1 c.-142T>C variant (rs755968566) is reported in individuals with chronic pancreatitis and absent from control individuals (Boulling 2011, Derikx 2015, Keiles 2006). This variant is also reported in ClinVar (Variation ID: 239502). Functional characterization shows this variant causes a decrease in promoter activity (Boulling 2011, Derikx 2015). This variant is found in the general population with an overall allele frequency of 0.02% (5/31408 alleles) in the Genome Aggregation Database. The c.-142T>C variant was predicted to disrupt the putative HNF1-binding sequence, and in vitro cross-competition and super shift assays support this prediction (Boulling 2011). However, 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 Derikx MHM 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 Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641 -

SPINK1-related disorder Uncertain:1

Mar 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPINK1 c.-142T>C variant is located in the 5' untranslated region. This variant has been reported in the heterozygous state in individuals with chronic pancreatitis (Keiles et al 2006. PubMed ID: 17003641; Boulling et al. 2011. PubMed ID: 21610753). Functional studies suggest the c.-142T>C variant disrupts HNF1 transcription factor binding which results in decreased SPINK1 expression (Boulling et al. 2011. PubMed ID: 21610753; Derikx et al. 2015. PubMed ID: 25792561). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. SPINK1 exhibits complicated inheritance in which autosomal recessive and dominant inheritance (with reduced penetrance) have been observed in patients with chronic pancreatitis, as well as possible digenic inheritance with other genes associated with chronic pancreatitis (eg. CFTC, CFTR, PRSS1 see Zou. 2018. PubMed ID: 30420730). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.78

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: rs755968566; hg19: chr5-147211282;