chr5-147831542-C-G

Position:

• chr5-147831542-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000296695.10(SPINK1):​c.36G>C​(p.Leu12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0053 in 1,613,622 control chromosomes in the GnomAD database, including 418 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (238 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (180 hom.)
• Consequence: SPINK1 ENST00000296695.10 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.85

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001957178).
• BP6: Variant 5-147831542-C-G is Benign according to our data. Variant chr5-147831542-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 36781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-147831542-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.36G>C	p.Leu12Phe	missense_variant	1/4	ENST00000296695.10	NP_001366539.1
LOC124901101	XR_007058987.1	n.500C>G		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.36G>C	p.Leu12Phe	missense_variant	1/4	1	NM_001379610.1	ENSP00000296695	P1
SPINK1	ENST00000510027.2	c.36G>C	p.Leu12Phe	missense_variant	1/3	3		ENSP00000427376

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4419 AN: 152160 Hom.: 238 Cov.: 33

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.00745 AC: 1866 AN: 250630 Hom.: 103 AF XY: 0.00514 AC XY: 696 AN XY: 135444

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.00394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00283 AC: 4131 AN: 1461344 Hom.: 180 Cov.: 30 AF XY: 0.00240 AC XY: 1743 AN XY: 726996

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00648

GnomAD4 genome AF: 0.0291 AC: 4427 AN: 152278 Hom.: 238 Cov.: 33 AF XY: 0.0276 AC XY: 2057 AN XY: 74450

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.00468 Hom.: 28

Bravo AF: 0.0331

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0978 AC: 431

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00919 AC: 1116

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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	Ambry Genetics	Feb 24, 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. -

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2018	This variant is associated with the following publications: (PMID: 27086061, 17568390, 20981092, 28994706, 17274009, 17003641) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 15, 2017	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.64	P;.
Vest4		0.16
MutPred		0.77		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.85
MPC		0.16
ClinPred		0.0089	T
GERP RS		3.1
Varity_R		0.080
gMVP		0.63

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: rs35877720; hg19: chr5-147211105;