rs190219062

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001379610.1(SPINK1):c.-22C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00083 in 1,613,012 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00087 ( 1 hom. )

Consequence

SPINK1
NM_001379610.1 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.0980

Publications

3 publications found

Variant links:

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, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
tropical pancreatitis
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

SPINK1 links:

LOC124901101 (HGNC:):

LOC124901101 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 5-147831599-G-A is Benign according to our data. Variant chr5-147831599-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 239504.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000486 (74/152330) while in subpopulation NFE AF = 0.000911 (62/68034). AF 95% confidence interval is 0.000729. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 74 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1 link	c.-22C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10 link	c.-22C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_001379610.1	ENSP00000296695.5		P00995
SPINK1	ENST00000510027.2 link	c.-22C>T		5_prime_UTR_variant	Exon 1 of 3	3		ENSP00000427376.1		D6RIU5

Frequencies

GnomAD3 genomes

AF:

0.000486

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000489

AC:

122

AN:

249640

AF XY:

0.000504

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000142

Gnomad NFE exome

AF:

0.000965

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000865

AC:

1264

AN:

1460682

Hom.:

Cov.:

AF XY:

0.000872

AC XY:

634

AN XY:

726658

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33442

American (AMR)

AF:

0.000201

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39542

South Asian (SAS)

AF:

0.000128

AC:

AN:

86214

European-Finnish (FIN)

AF:

0.000208

AC:

AN:

52996

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00107

AC:

1186

AN:

1111586

Other (OTH)

AF:

0.000663

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

139

208

278

347

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000486

AC:

AN:

152330

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41562

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000753

Hom.:

Bravo

AF:

0.000552

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Benign:3

May 11, 2021

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jun 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Uncertain:1Benign:1

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

7.8

(source)

DANN

Benign

0.83

PhyloP100

0.098

PromoterAI

0.0036

Neutral

(source)

Mutation Taster

=299/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over