rs114094661

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379610.1(SPINK1):c.194+184T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 526,370 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 12 hom., cov: 32)

Exomes 𝑓: 0.013 ( 57 hom. )

Consequence

SPINK1
NM_001379610.1 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.225

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 5-147827838-A-T is Benign according to our data. Variant chr5-147827838-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1588/152286) while in subpopulation NFE AF = 0.0172 (1172/68016). AF 95% confidence interval is 0.0164. There are 12 homozygotes in GnomAd4. There are 706 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1588 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1 link	c.194+184T>A		intron_variant	Intron 3 of 3	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPINK1	ENST00000296695.10 link	c.194+184T>A	intron_variant	Intron 3 of 3	1	NM_001379610.1	ENSP00000296695.5	P00995
SPINK1	ENST00000510027.2 link	c.*180T>A	3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000427376.1	D6RIU5
SPINK1	ENST00000505722.1 link	n.109+184T>A	intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1587

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.00589

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0172

Gnomad OTH

AF:

0.0139

GnomAD4 exome

AF:

0.0130

AC:

4863

AN:

374084

Hom.:

Cov.:

AF XY:

0.0127

AC XY:

2519

AN XY:

197978

show subpopulations

African (AFR)

AF:

0.00376

AC:

AN:

10896

American (AMR)

AF:

0.00658

AC:

AN:

14138

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

129

AN:

11560

East Asian (EAS)

AF:

0.00

AC:

AN:

26544

South Asian (SAS)

AF:

0.00476

AC:

156

AN:

32758

European-Finnish (FIN)

AF:

0.00661

AC:

148

AN:

22382

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

1640

European-Non Finnish (NFE)

AF:

0.0172

AC:

3991

AN:

232218

Other (OTH)

AF:

0.0138

AC:

303

AN:

21948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

220

440

660

880

1100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.0104

AC:

1588

AN:

152286

Hom.:

Cov.:

AF XY:

0.00948

AC XY:

706

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41568

American (AMR)

AF:

0.00588

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00580

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0172

AC:

1172

AN:

68016

Other (OTH)

AF:

0.0137

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

150

226

301

376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0156

Hom.:

Bravo

AF:

0.00971

Asia WGS

AF:

0.000290

AC:

AN:

3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Benign:3

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Jul 06, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10982753, 28472998) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.64

(source)

DANN

Benign

0.65

PhyloP100

-0.23

Mutation Taster

=100/0

polymorphism

(source)

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

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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