rs1379675813

Positions:

• chr5-147828079-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000296695.10(SPINK1):​c.137T>A​(p.Val46Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,346 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V46L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPINK1 ENST00000296695.10 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.44

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.137T>A	p.Val46Asp	missense_variant	3/4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.137T>A	p.Val46Asp	missense_variant	3/4	1	NM_001379610.1	ENSP00000296695	P1
SPINK1	ENST00000510027.2	c.137T>A	p.Val46Asp	missense_variant	3/3	3		ENSP00000427376
SPINK1	ENST00000505722.1	n.52T>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461346 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 06, 2017	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been reported in an individual affected with idiopathic recurrent acute pancreatitis (PMID: 25206283). This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with aspartic acid at codon 46 of the SPINK1 protein (p.Val46Asp). The valine residue is highly conserved and there is a large physicochemical difference between valine and aspartic acid. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2021	The p.V46D variant (also known as c.137T>A), located in coding exon 3 of the SPINK1 gene, results from a T to A substitution at nucleotide position 137. The valine at codon 46 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant was identified in a 20yr old Mexican male who presented with IRAP and pancreatic calcifications (Pelaez-Luna M et al.World J. Gastroenterol. 2014;20(33):11788-92). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 10, 2018

The SPINK1 c.137T>A; p.Val46Asp variant is reported in the literature in a single individual affected with idiopathic recurrent acute pancreatitis, in whom it was presumed to have occurred de novo (Pelaez-Luna 2014). This variant is also reported in ClinVar (Variation ID: 528769), but it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The valine at codon 46 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Val46Asp variant is uncertain at this time. References: Pelaez-Luna M et al. PRSS1 and SPINK1 mutations in idiopathic chronic and recurrent acute pancreatitis. World J Gastroenterol. 2014 Sep 7;20(33):11788-92. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.50	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.81
MutPred		0.88		Gain of disorder (P = 0.017);Gain of disorder (P = 0.017);
MVP		0.89
MPC		0.16
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs1379675813; hg19: chr5-147207642;