Genetic Variant SPINK1:p.Pro55Ser (chr5-147828053-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P55P) has been classified 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:16O:1

Conservation

PhyloP100: -7.04

Publications

60 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 -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 Benign/Likely_benign. ClinVar VariationId is 36778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 567 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.163C>T	p.Pro55Ser	missense	Exon 3 of 4	NP_001366539.1	P00995
SPINK1	NM_001354966.2		c.163C>T	p.Pro55Ser	missense	Exon 4 of 5	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.163C>T	p.Pro55Ser	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.163C>T	p.Pro55Ser	missense	Exon 3 of 4	ENSP00000296695.5	P00995
SPINK1	ENST00000510027.2	TSL:3	c.163C>T	p.Pro55Ser	missense	Exon 3 of 3	ENSP00000427376.1	D6RIU5
SPINK1	ENST00000505722.1	TSL:2	n.78C>T		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes

AF:

0.00448

AC:

1123

AN:

250482

AF XY:

0.00493

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 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

African (AFR)

AF:

0.000896

AC:

AN:

33468

American (AMR)

AF:

0.00239

AC:

107

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26114

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39584

South Asian (SAS)

AF:

0.00675

AC:

582

AN:

86232

European-Finnish (FIN)

AF:

0.00299

AC:

159

AN:

53178

Middle Eastern (MID)

AF:

0.00608

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00696

AC:

7739

AN:

1111706

Other (OTH)

AF:

0.00699

AC:

422

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

412

825

1237

1650

2062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

304

608

912

1216

1520

<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:

0.00373

AC:

567

AN:

152180

Hom.:

Cov.:

AF XY:

0.00370

AC XY:

275

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00104

AC:

AN:

41532

American (AMR)

AF:

0.00307

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00540

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00236

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00609

AC:

414

AN:

67990

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00497

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (8)

not provided (6)

not specified (1)

SPINK1-related disorder (1)

Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.0010

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.12

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0021

LIST_S2

Benign

0.83

M_CAP

Benign

0.013

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.99

PhyloP100

-7.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.77

REVEL

Benign

0.12

Sift

Benign

0.75

Sift4G

Benign

0.70

Polyphen

0.012

Vest4

0.060

MVP

0.15

MPC

0.019

ClinPred

0.0075

GERP RS

-9.8

Varity_R

0.081

gMVP

0.73

Mutation Taster

=97/3

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