rs779832256

Variant names:

• chr5-147831724-T-C
• rs779832256
• NM_001354966.2:c.-147A>G

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.-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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2 O:1
• Conservation: PhyloP100: 3.28

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]

ACMG classification

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001354966.2	c.-147A>G		5_prime_UTR_variant	Exon 2 of 5		NP_001341895.1
SPINK1	NM_003122.5	c.-147A>G		5_prime_UTR_variant	Exon 2 of 5		NP_003113.2
SPINK1	XM_047417625.1	c.-147A>G		5_prime_UTR_variant	Exon 3 of 6		XP_047273581.1
SPINK1	XM_047417626.1	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.: 2 Cov.: 33

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.: 6 Cov.: 30 AF XY: 0.000666 AC XY: 446 AN XY: 670008

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.: 2 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74490

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.: 0

Bravo AF: 0.000733

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jul 08, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2 Other:1

Jun 25, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

May 08, 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 (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

Sep 28, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis;C1842402:Tropical pancreatitis Benign:1

Feb 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SPINK1-related disorder Benign:1

Feb 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	17
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

Other links and lift over

dbSNP: rs779832256; hg19: chr5-147211287;