chr5-147831577-T-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001379610.1(SPINK1):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

SPINK1
NM_001379610.1 initiator_codon

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 3.28

Publications

4 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, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
tropical pancreatitis
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

SPINK1 links:

LOC124901101 (HGNC:):

LOC124901101 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-147831577-T-A is Pathogenic according to our data. Variant chr5-147831577-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496201.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 4	1	NM_001379610.1	ENSP00000296695.5		P00995
SPINK1	ENST00000510027.2 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 3	3		ENSP00000427376.1		D6RIU5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Pathogenic:3

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496201). Disruption of the initiator codon has been observed in individual(s) with chronic pancreatitis (PMID: 10835640,18172691). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPINK1 mRNA. There are no downstream in-frame methionine residues; therefore, it is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPINK1 are known to be pathogenic (PMID: 22572128,17681820). -

Aug 19, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the SPINK1 gene and results from an A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). This variant was reported in a patient with idiopathic chronic pancreatitis and was seen in conjunction with SPINK1 p.N34S (phase unknown) and CTRC c.494-10C>T (Masson E et al. Hum Genet 2008 Feb;123(1):83-91). A different variant that also abolishes the initiation codon was identified in a patient with hereditary chronic pancreatitis (Witt H et a. Nat Genet 2000 Jun;25(2):213-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:1Uncertain:1

Jul 31, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The SPINK1 c.1A>T (p.Met1Leu) variant involves the alteration of a conserved nucleotide and the start codon. There is no second Met in SPINK1 protein, suggesting the abolishment of the Met1 is likely to be damaging. In consistency with this prediction, 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 119498 control chromosomes and has been reported in at least one patient with chronic pancreatitis with co-occurrence of a pathogenic variant SPINK1 p.Asn34Ser (Masson_2008). Another start codon loss, p.Met1Thr, has been reported to associate with chronic pancreatitis (HGMD database). Taken together, this variant is classified as VUS-possibly pathogenic until more information becomes available. -

Jul 03, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.21

T;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.23

PhyloP100

3.3

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.98

D;.

Vest4

0.69

MutPred

0.98

Gain of methylation at K2 (P = 0.0384);Gain of methylation at K2 (P = 0.0384);

MVP

0.85

ClinPred

0.99

GERP RS

4.0

PromoterAI

-0.11

Neutral

(source)

Varity_R

0.89

gMVP

0.78

Mutation Taster

=20/180

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over