5-147828022-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001379610.1(SPINK1):c.194G>A(p.Arg65Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,609,898 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R65W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

SPINK1
NM_001379610.1 missense, splice_region

Scores

Splicing: ADA: 0.8899

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:9

Conservation

PhyloP100: -1.44

Publications

21 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024398416).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000605 (92/152006) while in subpopulation NFE AF = 0.00102 (69/67950). AF 95% confidence interval is 0.000822. There are 0 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 92 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.194G>A	p.Arg65Gln	missense splice_region	Exon 3 of 4	NP_001366539.1	P00995
SPINK1	NM_001354966.2		c.194G>A	p.Arg65Gln	missense splice_region	Exon 4 of 5	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.194G>A	p.Arg65Gln	missense splice_region	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.194G>A	p.Arg65Gln	missense splice_region	Exon 3 of 4	ENSP00000296695.5	P00995
SPINK1	ENST00000510027.2	TSL:3	c.194G>A	p.Arg65Gln	missense	Exon 3 of 3	ENSP00000427376.1	D6RIU5
SPINK1	ENST00000505722.1	TSL:2	n.109G>A		splice_region non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000606

AC:

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.000546

AC:

136

AN:

248944

AF XY:

0.000528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000330

Gnomad NFE exome

AF:

0.000951

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000731

AC:

1066

AN:

1457892

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

496

AN XY:

725390

show subpopulations

African (AFR)

AF:

0.0000899

AC:

AN:

33368

American (AMR)

AF:

0.000224

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39518

South Asian (SAS)

AF:

0.000268

AC:

AN:

85960

European-Finnish (FIN)

AF:

0.000435

AC:

AN:

52866

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.000881

AC:

978

AN:

1109484

Other (OTH)

AF:

0.000465

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000605

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41484

American (AMR)

AF:

0.0000655

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000418

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.000473

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00102

AC:

AN:

67950

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0545

Hom.:

2348

Bravo

AF:

0.000570

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hereditary pancreatitis (3)

Hereditary pancreatitis;C1842402:Tropical pancreatitis (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Benign

9.3

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.13

Eigen

Benign

-0.82

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.42

M_CAP

Benign

0.019

MetaRNN

Benign

0.024

MetaSVM

Benign

-0.98

PhyloP100

-1.4

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

REVEL

Uncertain

0.45

Sift

Benign

0.33

Sift4G

Benign

0.39

Polyphen

0.0

Vest4

0.12

MVP

0.64

MPC

0.020

ClinPred

0.016

GERP RS

-3.3

Varity_R

0.17

gMVP

0.52

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Pathogenic

0.79

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