Genetic Variant NM_001379610.1:c.194+2T>C (chr5-147828020-A-G) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 16P and 5B. PVS1PP5_Very_StrongBS1_SupportingBS2

The NM_001379610.1(SPINK1):c.194+2T>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000114 in 1,609,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SPINK1
NM_001379610.1 splice_donor, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 4.35

Publications

115 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: Pathogenic. The variant received 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 5-147828020-A-G is Pathogenic according to our data. Variant chr5-147828020-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 132142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000158 (24/152326) while in subpopulation EAS AF = 0.00309 (16/5186). AF 95% confidence interval is 0.00193. There are 0 homozygotes in GnomAd4. There are 14 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 24 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	Effect	Exon Rank	Protein	UniProt
SPINK1	NM_001379610.1	MANE Select	c.194+2T>C	splice_donor intron	N/A	NP_001366539.1	P00995
SPINK1	NM_001354966.2		c.194+2T>C	splice_donor intron	N/A	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.194+2T>C	splice_donor intron	N/A	NP_003113.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.194+2T>C		splice_donor intron	N/A	ENSP00000296695.5	P00995
SPINK1	ENST00000510027.2	TSL:3	c.196T>C	p.Ter66Argext*?	stop_lost	Exon 3 of 3	ENSP00000427376.1	D6RIU5
SPINK1	ENST00000505722.1	TSL:2	n.109+2T>C		splice_donor intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000313

AC:

AN:

248892

AF XY:

0.000253

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00335

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000109

AC:

159

AN:

1456778

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

724932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33324

American (AMR)

AF:

0.0000224

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26064

East Asian (EAS)

AF:

0.00207

AC:

AN:

39520

South Asian (SAS)

AF:

0.000151

AC:

AN:

85916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52858

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000505

AC:

AN:

1108502

Other (OTH)

AF:

0.000116

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000158

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41586

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00309

AC:

AN:

5186

South Asian (SAS)

AF:

0.000414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000335

Hom.:

Bravo

AF:

0.000212

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000288

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (6)

not provided (5)

Hereditary pancreatitis;C1842402:Tropical pancreatitis (2)

Chronic pancreatitis (1)

Diabetes mellitus (1)

SPINK1-related disorder (1)

Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

PhyloP100

4.3

GERP RS

4.9

Mutation Taster

=32/168

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 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