rs111966833

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379610.1(SPINK1):c.163C>T(p.Pro55Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00599 in 1,613,290 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 49 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15O:1

Conservation

PhyloP100: -7.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010206819).

BP6

Variant 5-147828053-G-A is Benign according to our data. Variant chr5-147828053-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-147828053-G-A is described in Lovd as [Likely_benign]. Variant chr5-147828053-G-A is described in Lovd as [Benign]. Variant chr5-147828053-G-A is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00373 (567/152180) while in subpopulation NFE AF= 0.00609 (414/67990). AF 95% confidence interval is 0.0056. There are 3 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 568 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK1	NM_001379610.1 linkuse as main transcript	c.163C>T	p.Pro55Ser	missense_variant	3/4	ENST00000296695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
SPINK1	ENST00000296695.10 linkuse as main transcript	c.163C>T	p.Pro55Ser	missense_variant	3/4	1	NM_001379610.1	P1
SPINK1	ENST00000510027.2 linkuse as main transcript	c.163C>T	p.Pro55Ser	missense_variant	3/3	3
SPINK1	ENST00000505722.1 linkuse as main transcript	n.78C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.00374

AC:

568

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00540

Gnomad FIN

AF:

0.00236

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00448

AC:

1123

AN:

250482

Hom.:

AF XY:

0.00493

AC XY:

667

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.000895

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00631

Gnomad FIN exome

AF:

0.00256

Gnomad NFE exome

AF:

0.00651

Gnomad OTH exome

AF:

0.00393

GnomAD4 exome

AF:

0.00623

AC:

9101

AN:

1461110

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

4459

AN XY:

726864

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.00239

Gnomad4 ASJ exome

AF:

0.000957

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00675

Gnomad4 FIN exome

AF:

0.00299

Gnomad4 NFE exome

AF:

0.00696

Gnomad4 OTH exome

AF:

0.00699

GnomAD4 genome

AF:

0.00373

AC:

567

AN:

152180

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

275

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.00104

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00540

Gnomad4 FIN

AF:

0.00236

Gnomad4 NFE

AF:

0.00609

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00544

Hom.:

Bravo

AF:

0.00397

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00430

AC:

ExAC

AF:

0.00446

AC:

541

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00753

EpiControl

AF:

0.00611

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Benign:7Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 11, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2016	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. -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	SPINK1: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2020	This variant is associated with the following publications: (PMID: 17568390, 22427236, 17525091, 27253233, 28994706, 15764155, 12360464, 10982753, 20977904, 26100556, 11265669, 12822871, 12634855, 23951356, 10835640, 10691414) -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Tropical pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

SPINK1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2020

This variant is classified as 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

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

Cadd

Benign

0.0010

Dann

Benign

0.14

DEOGEN2

Benign

0.12

T;.

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.83

T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.77

N;N

REVEL

Benign

0.12

Sift

Benign

0.75

T;T

Sift4G

Benign

0.70

T;T

Polyphen

0.012

B;.

Vest4

0.060

MVP

0.15

MPC

0.019

ClinPred

0.0075

GERP RS

-9.8

Varity_R

0.081

gMVP

0.73

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.

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