chr5-147824701-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001379610.1(SPINK1):c.200G>A(p.Arg67His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,846 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0096 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 29 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 0.0970

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
tropical pancreatitis
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

SPINK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005965978).

BP6

Variant 5-147824701-C-T is Benign according to our data. Variant chr5-147824701-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132716.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0096 (1461/152150) while in subpopulation AFR AF = 0.0315 (1307/41514). AF 95% confidence interval is 0.0301. There are 13 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1461 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1 link	c.200G>A	p.Arg67His	missense_variant	Exon 4 of 4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10 link	c.200G>A	p.Arg67His	missense_variant	Exon 4 of 4	1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000505722.1 link	n.115G>A		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00956

AC:

1454

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00675

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00256

AC:

640

AN:

250356

AF XY:

0.00182

show subpopulations

Gnomad AFR exome

AF:

0.0318

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.00117

AC:

1711

AN:

1461696

Hom.:

Cov.:

AF XY:

0.00104

AC XY:

755

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.0344

AC:

1152

AN:

33474

American (AMR)

AF:

0.00257

AC:

115

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000255

AC:

284

AN:

1111926

Other (OTH)

AF:

0.00232

AC:

140

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00960

AC:

1461

AN:

152150

Hom.:

Cov.:

AF XY:

0.00949

AC XY:

706

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0315

AC:

1307

AN:

41514

American (AMR)

AF:

0.00674

AC:

103

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000416

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68014

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00377

Hom.:

Bravo

AF:

0.0108

TwinsUK

AF:

0.000809

AC:

ESP6500AA

AF:

0.0334

AC:

147

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00305

AC:

370

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Benign:6

Mar 21, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Dec 28, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:3Benign:1

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BP4, PM5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Aug 01, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SPINK1 c.200G>A (p.Arg67His) 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 0.002 in 1606876 control chromosomes, predominantly at a frequency of 0.033 within the African or African-American subpopulation in the gnomAD database (v4.1 dataset), including 41 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in SPINK1 causing (recessive) Chronic Pancreatitis phenotype (0.022). However, in the United States, Europe, and India, a high-risk haplotype containing SPINK1 p.Asn34Ser (c.101A>G) is common, with a minor allele frequency as high as 3% (Gene Reviews), suggesting that an allele frequency of 3% for this missense variant, as observed in the African gnomAD subpopulation, should not automatically rule out pathogenicity. c.200G>A has been reported in the literature in individuals affected with chronic or acute recurrent pancreatitis (e.g. Werlin_2014, Boulling_2012, Giefer_2017, Jalaly_2017, Muller_2019, Scheers_2019). These reports, however, do not provide supportive evidence about association of the variant with the disease. In addition, in a recent report a proband with early onset chronic pancreatitis didn't inherit the variant from a parent who carried the variant but had much later onset of the disease (Hamada_2022). At least two publications reported experimental evidence evaluating the variant impact, and demonstrated no splice change or mRNA expression level alteration (Wu_2017), but loss of PST1 protein (encoded by SPINK1) via Western blotting; however, authors used a monoclonal antibody in these expression studies which might be subject to loss of binding with certain amino acid substitutions, so the perceived reduction in PST1 levels based on this experiment alone could not be accurately assessed (Boulling_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22343981, 22749696, 28502372, 18580441, 28440306, 33097431, 22526274, 31628023, 31391146, 33515547, 25383785, 28994706, 34923708, 35974416). ClinVar contains an entry for this variant (Variation ID: 132716). Based on the evidence outlined above, the variant was classified as likely benign.

SPINK1-related disorder

Benign:1

Feb 04, 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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.61

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0060

MetaSVM

Benign

-1.0

PhyloP100

0.097

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.3

Sift

Benign

0.27

Sift4G

Benign

0.14

Vest4

0.71

ClinPred

0.0092

GERP RS

3.3

Varity_R

0.16

gMVP

0.54

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over