5-147828115-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001379610.1(SPINK1):c.101A>G(p.Asn34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,612,638 control chromosomes in the GnomAD database, including 131 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 Conflicting classifications of pathogenicity,association,risk factor (no stars).

Frequency

Genomes: 𝑓 0.0082 ( 7 hom., cov: 32)

Exomes 𝑓: 0.011 ( 124 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; association; risk factor criteria provided, conflicting classifications P:18U:4B:1O:5

Conservation

PhyloP100: -3.75

Publications

318 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, MODERATE, SUPPORTIVE, NO_KNOWN Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

SPINK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005059749).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00825 (1256/152316) while in subpopulation SAS AF = 0.0176 (85/4816). AF 95% confidence interval is 0.0146. There are 7 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 1256 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379610.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK1	NM_001379610.1	MANE Select	c.101A>G	p.Asn34Ser	missense	Exon 3 of 4	NP_001366539.1	P00995
SPINK1	NM_001354966.2		c.101A>G	p.Asn34Ser	missense	Exon 4 of 5	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.101A>G	p.Asn34Ser	missense	Exon 4 of 5	NP_003113.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.101A>G	p.Asn34Ser	missense	Exon 3 of 4	ENSP00000296695.5	P00995
SPINK1	ENST00000510027.2	TSL:3	c.101A>G	p.Asn34Ser	missense	Exon 3 of 3	ENSP00000427376.1	D6RIU5
SPINK1	ENST00000505722.1	TSL:2	n.16A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00825

AC:

1256

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00419

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00596

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0110

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00906

AC:

2262

AN:

249598

AF XY:

0.00989

show subpopulations

Gnomad AFR exome

AF:

0.00241

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.000899

Gnomad EAS exome

AF:

0.00279

Gnomad FIN exome

AF:

0.0172

Gnomad NFE exome

AF:

0.00964

Gnomad OTH exome

AF:

0.00772

GnomAD4 exome

AF:

0.0113

AC:

16555

AN:

1460322

Hom.:

124

Cov.:

AF XY:

0.0117

AC XY:

8486

AN XY:

726450

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33456

American (AMR)

AF:

0.00212

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00111

AC:

AN:

26102

East Asian (EAS)

AF:

0.00422

AC:

167

AN:

39552

South Asian (SAS)

AF:

0.0214

AC:

1845

AN:

86146

European-Finnish (FIN)

AF:

0.0159

AC:

843

AN:

53072

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0115

AC:

12826

AN:

1111188

Other (OTH)

AF:

0.0115

AC:

692

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

740

1480

2220

2960

3700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

524

1048

1572

2096

2620

<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:

0.00825

AC:

1256

AN:

152316

Hom.:

Cov.:

AF XY:

0.00840

AC XY:

626

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41574

American (AMR)

AF:

0.00418

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.00578

AC:

AN:

5188

South Asian (SAS)

AF:

0.0176

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0179

AC:

190

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0110

AC:

750

AN:

68026

Other (OTH)

AF:

0.0113

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

116

174

232

290

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:

0.00931

Hom.:

Bravo

AF:

0.00661

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.00912

AC:

1107

Asia WGS

AF:

0.0370

AC:

128

AN:

3478

EpiCase

AF:

0.00780

EpiControl

AF:

0.00878

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity; association; risk factor

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (20)

not provided (3)

Tropical pancreatitis (2)

Finnish congenital nephrotic syndrome (1)

Pancreatitis, chronic, susceptibility to (1)

Pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0010

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.081

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0051

MetaSVM

Benign

-0.93

PhyloP100

-3.8

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.68

REVEL

Benign

0.20

Sift

Benign

0.42

Sift4G

Benign

0.78

Polyphen

0.010

Vest4

0.053

MVP

0.43

MPC

0.018

ClinPred

0.0019

GERP RS

-3.9

Varity_R

0.098

gMVP

0.41

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over