rs35877720

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379610.1(SPINK1):c.36G>C(p.Leu12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,613,622 control chromosomes in the GnomAD database, including 418 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L12S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.029 ( 238 hom., cov: 33)

Exomes 𝑓: 0.0028 ( 180 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.85

Publications

5 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:

LOC124901101 (HGNC:):

LOC124901101 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=0.001957178).

BP6

Variant 5-147831542-C-G is Benign according to our data. Variant chr5-147831542-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0989 is higher than 0.05.

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.36G>C	p.Leu12Phe	missense	Exon 1 of 4	NP_001366539.1	P00995
SPINK1	NM_001354966.2		c.36G>C	p.Leu12Phe	missense	Exon 2 of 5	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.36G>C	p.Leu12Phe	missense	Exon 2 of 5	NP_003113.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.36G>C	p.Leu12Phe	missense	Exon 1 of 4	ENSP00000296695.5	P00995
	SPINK1	ENST00000510027.2	TSL:3	c.36G>C	p.Leu12Phe	missense	Exon 1 of 3	ENSP00000427376.1	D6RIU5

Frequencies

GnomAD3 genomes

AF:

0.0290

AC:

4419

AN:

152160

Hom.:

238

Cov.:

show subpopulations

Gnomad AFR

AF:

0.102

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00858

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0277

GnomAD2 exomes

AF:

0.00745

AC:

1866

AN:

250630

AF XY:

0.00514

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00394

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00283

AC:

4131

AN:

1461344

Hom.:

180

Cov.:

AF XY:

0.00240

AC XY:

1743

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.101

AC:

3370

AN:

33454

American (AMR)

AF:

0.00490

AC:

219

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39630

South Asian (SAS)

AF:

0.000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000115

AC:

128

AN:

1111836

Other (OTH)

AF:

0.00648

AC:

391

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

199

398

598

797

996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

204

306

408

510

<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:

0.0291

AC:

4427

AN:

152278

Hom.:

238

Cov.:

AF XY:

0.0276

AC XY:

2057

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.101

AC:

4215

AN:

41554

American (AMR)

AF:

0.00850

AC:

130

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68032

Other (OTH)

AF:

0.0303

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

201

403

604

806

1007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.00468

Hom.:

Bravo

AF:

0.0331

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0978

AC:

431

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00919

AC:

1116

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (6)

not provided (4)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.57

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

PhyloP100

1.9

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

REVEL

Benign

0.24

Sift

Uncertain

0.024

Sift4G

Uncertain

0.038

Polyphen

0.64

Vest4

0.16

MutPred

0.77

Loss of helix (P = 0.1299)

MVP

0.85

MPC

0.16

ClinPred

0.0089

GERP RS

3.1

PromoterAI

0.044

Neutral

(source)

Varity_R

0.080

gMVP

0.63

Mutation Taster

=99/1

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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