rs143014431

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001379610.1(SPINK1):ā€‹c.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

Genomes: š‘“ 0.00034 ( 0 hom., cov: 32)
Exomes š‘“: 0.00043 ( 0 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -0.0960
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.068697184).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000335 (51/152146) while in subpopulation NFE AF= 0.000661 (45/68030). AF 95% confidence interval is 0.000508. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. 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 51 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPINK1NM_001379610.1 linkc.198A>C p.Lys66Asn missense_variant Exon 4 of 4 ENST00000296695.10 NP_001366539.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPINK1ENST00000296695.10 linkc.198A>C p.Lys66Asn missense_variant Exon 4 of 4 1 NM_001379610.1 ENSP00000296695.5 P00995
SPINK1ENST00000505722.1 linkn.113A>C non_coding_transcript_exon_variant Exon 2 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.000335
AC:
51
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.000661
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000200
AC:
50
AN:
250312
Hom.:
0
AF XY:
0.000185
AC XY:
25
AN XY:
135352
show subpopulations
Gnomad AFR exome
AF:
0.000247
Gnomad AMR exome
AF:
0.000145
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:
0.000345
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000431
AC:
630
AN:
1461710
Hom.:
0
Cov.:
31
AF XY:
0.000414
AC XY:
301
AN XY:
727154
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000179
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:
0.000508
Gnomad4 OTH exome
AF:
0.000811
GnomAD4 genome
AF:
0.000335
AC:
51
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000661
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000302
Hom.:
0
Bravo
AF:
0.000272
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000148
AC:
18
EpiCase
AF:
0.000382
EpiControl
AF:
0.000415

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary pancreatitis Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 24, 2024This 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 submitterclinical testingAmbry GeneticsMay 22, 2024The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 11, 2025Variant 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 submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 15, 2024- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 29, 2019- -
SPINK1-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 29, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.48
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
10
DANN
Uncertain
0.98
DEOGEN2
Benign
0.17
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.37
T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.069
T
MetaSVM
Benign
-0.92
T
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-2.3
N
REVEL
Benign
0.17
Sift
Uncertain
0.021
D
Sift4G
Benign
0.15
T
Polyphen
0.30
B
Vest4
0.095
MutPred
0.80
Loss of ubiquitination at K66 (P = 0.0326);
MVP
0.43
MPC
0.074
ClinPred
0.032
T
GERP RS
-2.8
Varity_R
0.42
gMVP
0.74

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.

Other links and lift over

dbSNP: rs143014431; hg19: chr5-147204266; API