rs35737774

Positions:

• chr5-147828042-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000296695.10(SPINK1):​c.174C>T​(p.Cys58=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00748 in 1,612,588 control chromosomes in the GnomAD database, including 755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (417 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (338 hom.)
• Consequence: SPINK1 ENST00000296695.10 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.0340

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 5-147828042-G-A is Benign according to our data. Variant chr5-147828042-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-147828042-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.034 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.174C>T	p.Cys58=	synonymous_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.174C>T	p.Cys58=	synonymous_variant	3/4	1	NM_001379610.1	ENSP00000296695	P1
SPINK1	ENST00000510027.2	c.174C>T	p.Cys58=	synonymous_variant	3/3	3		ENSP00000427376
SPINK1	ENST00000505722.1	n.89C>T		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.0410 AC: 6237 AN: 151942 Hom.: 417 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0108 AC: 2708 AN: 250228 Hom.: 194 AF XY: 0.00796 AC XY: 1076 AN XY: 135260

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.00768

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.00639

GnomAD4 exome AF: 0.00398 AC: 5819 AN: 1460528 Hom.: 338 Cov.: 30 AF XY: 0.00346 AC XY: 2514 AN XY: 726630

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.00868

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.0000754

Gnomad4 NFE exome AF: 0.000265

Gnomad4 OTH exome AF: 0.00928

GnomAD4 genome AF: 0.0410 AC: 6242 AN: 152060 Hom.: 417 Cov.: 32 AF XY: 0.0403 AC XY: 2999 AN XY: 74340

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000530

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0203 Hom.: 75

Bravo AF: 0.0477

Asia WGS AF: 0.0130 AC: 44 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Benign:4

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 27, 2016	This alteration is classified as 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. -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 24, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.28

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: rs35737774; hg19: chr5-147207605;