Variant chr5-147831719-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 2.42

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BS2

High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1 linkuse as main transcript	c.-142T>C		upstream_gene_variant		ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10 linkuse as main transcript	c.-142T>C		upstream_gene_variant		1	NM_001379610.1	ENSP00000296695.5		P00995

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.000185

AC XY:

124

AN XY:

671976

show subpopulations

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:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74490

show subpopulations

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.:

Bravo

AF:

0.000234

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2018	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. Experimental studies have shown that this non-coding change disrupts SPINK1 protein function (PMID:¬†21610753,¬†28556356,¬†25792561). This variant has been observed in individuals affected with pancreatitis (PMID: 17003641, 21610753). ClinVar contains an entry for this variant (Variation ID: 239502). This variant is not present in population databases (ExAC no frequency). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2021	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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 29, 2023

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Apr 24, 2023

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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2024

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over