rs369163833

Positions:

• chr5-147831577-T-A
• chr5-147831577-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001379610.1(SPINK1):​c.1A>T​(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 3.28

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]

LOC124901101 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 496201.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.1A>T	p.Met1?	start_lost	1/4	ENST00000296695.10	NP_001366539.1
LOC124901101	XR_007058987.1	n.535T>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.1A>T	p.Met1?	start_lost	1/4	1	NM_001379610.1	ENSP00000296695	P1
SPINK1	ENST00000510027.2	c.1A>T	p.Met1?	start_lost	1/3	3		ENSP00000427376

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33

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.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74370

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2023	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). This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with chronic pancreatitis (PMID: 10835640,18172691). ClinVar contains an entry for this variant (Variation ID: 496201). 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. -

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 31, 2017	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.23	D
MutationTaster	Benign	1.0	D;D
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	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs369163833; hg19: chr5-147211140;