5-147829667-A-G

Position:

• chr5-147829667-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001379610.1(SPINK1):​c.56-37T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 1,590,006 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,risk factor (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (102 hom.)
• Consequence: SPINK1 NM_001379610.1 intron
• Clinical Significance: Benign/Likely benign; risk factor criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -0.216

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 5-147829667-A-G is Benign according to our data. Variant chr5-147829667-A-G is described in ClinVar as [Likely_benign, risk_factor]. Clinvar id is 239507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0076 (1158/152330) while in subpopulation SAS AF= 0.0153 (74/4832). AF 95% confidence interval is 0.0125. There are 6 homozygotes in gnomad4. There are 580 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1158 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.56-37T>C		intron_variant		ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.56-37T>C		intron_variant		1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000510027.2	c.56-37T>C		intron_variant		3		ENSP00000427376.1

Frequencies

GnomAD3 genomes AF: 0.00761 AC: 1158 AN: 152212 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00998

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00825 AC: 2055 AN: 249204 Hom.: 18 AF XY: 0.00898 AC XY: 1210 AN XY: 134712

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.000897

Gnomad EAS exome AF: 0.00219

Gnomad SAS exome AF: 0.0171

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00873

Gnomad OTH exome AF: 0.00724

GnomAD4 exome AF: 0.00993 AC: 14282 AN: 1437676 Hom.: 102 Cov.: 27 AF XY: 0.0102 AC XY: 7332 AN XY: 716858

Gnomad4 AFR exome AF: 0.00109

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.00112

Gnomad4 EAS exome AF: 0.00410

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.0158

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00961

GnomAD4 genome AF: 0.00760 AC: 1158 AN: 152330 Hom.: 6 Cov.: 33 AF XY: 0.00779 AC XY: 580 AN XY: 74500

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00541

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.00998

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00720 Hom.: 1

Bravo AF: 0.00604

Asia WGS AF: 0.0340 AC: 119 AN: 3476

ClinVar

Significance: Benign/Likely benign; risk factor

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
risk factor, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SPINK1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17107318; hg19: chr5-147209230;