Variant rs779832256 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_003122.5(SPINK1):c.-147A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,513,248 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 6 hom. )

Consequence

SPINK1
NM_003122.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2O:1

Conservation

PhyloP100: 3.28

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000742 (113/152332) while in subpopulation NFE AF= 0.000309 (21/68036). AF 95% confidence interval is 0.000207. There are 2 homozygotes in gnomad4. There are 47 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 113 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
SPINK1	NM_001354966.2 link	c.-147A>G	5_prime_UTR_variant	Exon 2 of 5	NP_001341895.1
SPINK1	NM_003122.5 link	c.-147A>G	5_prime_UTR_variant	Exon 2 of 5	NP_003113.2	P00995
SPINK1	XM_047417625.1 link	c.-147A>G	5_prime_UTR_variant	Exon 3 of 6	XP_047273581.1
SPINK1	XM_047417626.1 link	c.-147A>G	5_prime_UTR_variant	Exon 3 of 6	XP_047273582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000619

AC:

843

AN:

1360916

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

446

AN XY:

670008

show subpopulations

Gnomad4 AFR exome

AF:

0.000195

Gnomad4 AMR exome

AF:

0.000472

Gnomad4 ASJ exome

AF:

0.0214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000196

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.00159

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152332

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.0216

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000763

Hom.:

Bravo

AF:

0.000733

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 08, 2022	- -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 26, 2024	The SPINK1 c.-147A>G variant (rs779832256) is reported in the literature in individuals affected with pancreatitis or pancreatic cancer, but is also found in healthy controls (Boulling 2011, Derikx 2015, Keiles 2006, Slavin 2018). This variant is also reported in ClinVar (Variation ID: 239503), and is found in the general population with an overall allele frequency of 0.022% (7/31408 alleles) in the Genome Aggregation Database (v2.1.1). This variant occurs in the 5' untranslated region at a nucleotide that is weakly conserved, and in vitro reporter assays demonstrate reduced expression (Boulling 2011, Derikx 2015). However, whether reduced expression occurs in vivo or is sufficient for disease remains to be determined. Given available 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 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. 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. Slavin TP et al. The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes. Fam Cancer. 2018 Apr;17(2):235-245. PMID: 28687971. -

Hereditary pancreatitis

Uncertain:2Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2021	The c.-147A>G variant is located in the 5' untranslated region (5’ UTR) of the SPINK1 gene. This variant results from an A to G substitution 147 bases upstream from the first translated codon. This nucleotide position is highly conserved in available vertebrate species. The variant has been detected in multiple individuals with pancreatitis or pancreatic cancer (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Boulling A et al. Eur. J. Hum. Genet., 2011 Oct;19:1066-73; Slavin TP et al. Fam Cancer, 2018 04;17:235-245). 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. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 11-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2024	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 (rs779832256, gnomAD 1.7%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with chronic pancreatitis or pancreatic cancer (PMID: 17003641, 21610753, 28687971). ClinVar contains an entry for this variant (Variation ID: 239503). 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, 25792561, 28556356). 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. -

Tropical pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 28, 2023

- -

Hereditary pancreatitis;C1842402:Tropical pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 18, 2024

- -

SPINK1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.69

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

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