rs148954387

Variant names:

• chr5-147828020-A-G
• rs148954387
• NM_001379610.1:c.194+2T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-147828020-A-G
• chr5-147828020-A-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 20P and 5B. PVS1 PS3 PP5_Very_Strong BS1_Supporting BS2

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 (★★). ClinVar reports functional evidence for this variant: "SCV000253884: Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:18978175, 26719302)." and additional evidence is available in ClinVar.

• 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:16 O:1
• Conservation: PhyloP100: 4.35
• Publications: 121 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 15 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000253884: Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 18978175, 26719302).; SCV000918271: "These predictions are supported by multiple functional studies, Kume_2006 and Kereszturi_2009, found the variant to significantly affect splicing."; SCV001174384: A functional study found this mutation causes a splicing defect that significantly diminishes SPINK1 expression at the mRNA level and results in diminished trypsin inhibitor secretion (Kereszturi E et al. Gut, 2009 Apr;58:545-9).; SCV000605252: "Indeed, functional studies indicate a significant reduction of mRNA levels, skipping of exon 3, and undetectable levels of the SPINK1 protein (Kereszturi 2009, Kume 2006, Zou 2016)."; SCV004121291: "functional studies support its pathogenicity (Witt et al. 2000. PubMed ID: 10835640; Kereszturi et al. 2008. PubMed ID: 18978175; Sun et al. 2015. PubMed ID: 26632706)."
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	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

Sel.	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: 24 AN: 152208 Hom.: 0 Cov.: 32

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: 78 AN: 248892 AF XY: 0.000253

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.: 0 Cov.: 29 AF XY: 0.000109 AC XY: 79 AN XY: 724932

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.0000224 AC: 1 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00207 AC: 82 AN: 39520

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.0000505 AC: 56 AN: 1108502

Other (OTH) AF: 0.000116 AC: 7 AN: 60222

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5186

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000335 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Hereditary pancreatitis (6)
5	-	-	not provided (5)
2	-	-	Hereditary pancreatitis;C1842402:Tropical pancreatitis (2)
1	-	-	Chronic pancreatitis (1)
1	-	-	Diabetes mellitus (1)
1	-	-	SPINK1-related disorder (1)
1	-	-	Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.3
GERP RS		4.9
Mutation Taster		=32/168	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs148954387; hg19: chr5-147207583;