rs193922659

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_001379610.1(SPINK1):c.27del(p.Ser10ValfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

SPINK1
NM_001379610.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: -0.786

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:

LOC124901101 (HGNC:):

LOC124901101 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.

PP5

Variant 5-147831550-TG-T is Pathogenic according to our data. Variant chr5-147831550-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 36780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK1	NM_001379610.1 linkuse as main transcript	c.27del	p.Ser10ValfsTer6	frameshift_variant	1/4	ENST00000296695.10
LOC124901101	XR_007058987.1 linkuse as main transcript	n.509del		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK1	ENST00000296695.10 linkuse as main transcript	c.27del	p.Ser10ValfsTer6	frameshift_variant	1/4	1	NM_001379610.1	P1
SPINK1	ENST00000510027.2 linkuse as main transcript	c.27del	p.Ser10ValfsTer6	frameshift_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250684

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461392

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	This sequence change creates a premature translational stop signal (p.Ser10Valfs*6) in the SPINK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK1 are known to be pathogenic (PMID: 17681820, 22572128). This variant is present in population databases (rs193922659, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with chronic pancreatitis (PMID: 14722925, 22572128). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36780). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 12, 2021	Variant summary: SPINK1 c.27delC (p.Ser10ValfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 251284 control chromosomes (gnomAD and Marechal_2004). c.27delC has been reported in the literature in multiple individuals affected with Chronic Pancreatitis. In one family, the variant segregated with the disease in two generations and had penetrance as high as 75%, while in another family the variant seemed to act as a low-penetrance susceptibility factor (Marechal_2004). In a third family with chronic pancreatitis, the reported penetrance was for the variant was 44% (LaRusch_2012). These data indicate that the variant is very likely to be associated with chronic pancreatitis, albeit with variable penetrance. Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2023	The c.27delC pathogenic mutation, located in coding exon 1 of the SPINK1 gene, results from a deletion of one nucleotide at nucleotide position 27, causing a translational frameshift with a predicted alternate stop codon (p.S10Vfs*6). This mutation has been detected in two families with chronic pancreatitis with reduced penetrance (Le Maréchal C et al. Hum. Mutat., 2004 Feb;23:205; LaRusch J et al. JOP, 2012 May;13:258-62). In HEK293 cells, this mutation showed reduced mRNA levels compared to wild type (Wu H et al. Gut, 2017 12;66:2195-2196). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 28, 2023

The SPINK1 c.27delC; p.Ser10ValfsTer6 variant (rs193922659) is reported in multiple patients with hereditary pancreatitis (LaRusch 2012, Le Marechal 2004, Masson 2015, Rosendahl 2013). This variant is found in the heterozygous state in affected individuals, but is also present in relatives that do not develop pancreatitis, suggesting that the variant could be associated with an increased risk with pancreatitis even in a heterozygous state (LaRusch 2012, Le Marechal 2004). This variant is reported in ClinVar (Variation ID: 36780), and is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. References: LaRusch J et al. Whole exome sequencing identifies multiple, complex etiologies in an idiopathic hereditary pancreatitis kindred. JOP. 2012; 13(3):258-62. PMID: 22572128. Le Marechal C et al. Two novel severe mutations in the pancreatic secretory trypsin inhibitor gene (SPINK1) cause familial and/or hereditary pancreatitis. Hum Mutat. 2004; 23(2):205. PMID: 14722925. Masson E et al. Report of 2 CTRC Intronic Mutations Associated With Acute or Chronic Pancreatitis and Delineation of Their Pathogenic Molecular Mechanisms. Pancreas. 2015; 44(6):999-1001. PMID: 26166474. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013; 62(4):582-92. PMID: 22427236. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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