rs143014431
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_001379610.1(SPINK1):āc.198A>Cā(p.Lys66Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_001379610.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPINK1 | NM_001379610.1 | c.198A>C | p.Lys66Asn | missense_variant | Exon 4 of 4 | ENST00000296695.10 | NP_001366539.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000335 AC: 51AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000200 AC: 50AN: 250312Hom.: 0 AF XY: 0.000185 AC XY: 25AN XY: 135352
GnomAD4 exome AF: 0.000431 AC: 630AN: 1461710Hom.: 0 Cov.: 31 AF XY: 0.000414 AC XY: 301AN XY: 727154
GnomAD4 genome AF: 0.000335 AC: 51AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74330
ClinVar
Submissions by phenotype
Hereditary pancreatitis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2024 | This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 66 of the SPINK1 protein (p.Lys66Asn). This variant is present in population databases (rs143014431, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pancreatitis (PMID: 17003641, 28502372, 33515547). ClinVar contains an entry for this variant (Variation ID: 410699). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SPINK1 function (PMID: 22343981). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 22, 2024 | The p.K66N variant (also known as c.198A>C), located in coding exon 4 of the SPINK1 gene, results from an A to C substitution at nucleotide position 198. The lysine at codon 66 is replaced by asparagine, an amino acid with similar properties. This variant was reported in multiple individuals with chronic or recurrent pancreatitis (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Giefer MJ et al. J Pediatr, 2017 Jul;186:95-100). Functional studies suggest that the variant reduces protein expression; however, additional evidence is needed to confirm this finding (Boulling A et al. Pancreas, 2012 Mar;41:329-30). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 11, 2025 | Variant summary: SPINK1 c.198A>C (p.Lys66Asn) results in a non-conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250312 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SPINK1 causing Chronic Pancreatitis (0.0002 vs 0.022), allowing no conclusion about variant significance. c.198A>C has been reported in the literature in at least two children affected with pancreatitis, one 15-year-old caucasian male referred to genetic testing in whom no other sequence variant in PRSS1, SPINK1 or CFTR genes were identified (Keiles_2006), and in a 1-year-old evaluated as part of the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPIRRE) study in whom a co-occurring pathogenic SPINK1 variant (c.101A>G/p.Asn34Ser) was also identified (Giefer_2017). It has also been subsequently cited as a non-primary reference by others (example, Chua_2011, Chen_2012, Kume_2012, Szabo_2021). These data do not allow any conclusion about variant significance. Publications report experimental evidence evaluating an impact on protein function. One study reported a complete loss of expression of the protein product encoding the SPINK1 gene (PTS1) in human embryonic kidney 293T cells transfected with a mutant construct bearing this variant (Boulling_2012). The authors speculate that the possibility of reduced or lack of binding activity of the mutant protein to the monoclonal anti-hPST1 antibody used in their experimental system cannot be ruled out (Boulling_2007). Another study reported no difference in splicing or mRNA expression associated with this variant when compared to the wild type, thereby ruling out any impact of this missense variant on pre-mRNA splicing and/or mRNA stability (Wu_2017). The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 22526274, 22343981, 21952138, 22749696, 28502372, 28994706, 33515547, 35974416). ClinVar contains an entry for this variant (Variation ID: 410699). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary pancreatitis;C1842402:Tropical pancreatitis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 15, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 29, 2019 | - - |
SPINK1-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 29, 2024 | The SPINK1 c.198A>C variant is predicted to result in the amino acid substitution p.Lys66Asn. This variant has been reported in the heterozygous state in an individual with chronic pancreatitis and to co-occur with another SPINK1 variant (phase unknown) in an individual with early onset acute pancreatitis (Table 3, Keiles et al. 2006. PubMed ID: 17003641; Table III, Giefer et al. 2017. PubMed ID: 28502372). A full-length gene assay to assess pre-mRNA splicing suggests that this variant does not affect pre-mRNA splicing and/or mRNA stability (Table 1, Wu H et al. 2017. PubMed ID: 28994706). However, a study of protein expression in human embryonic kidney 293T (HEK293T) cells showed this variant causes complete loss of SPINK1 protein compared to control (Figure 1, Boulling et al. 2012. PubMed ID: 22343981). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be a primary cause of autosomal dominant disease. Conflicting interpretations of pathogenic and uncertain are present in the ClinVar database for the c.198A>C variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/410699). Although this variant may contribute to chronic pancreatitis phenotypes with reduced penetrance, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at