dbSNP rs199929811: SPINK1:c.88-23A>T (chr5-147828151-T-A) – ACMG Classification: Benign (-20 pts)

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.88-23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,561,578 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 8 hom. )

Consequence

SPINK1
NM_001379610.1 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.915

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, MODERATE, SUPPORTIVE, NO_KNOWN Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

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

This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 5-147828151-T-A is Benign according to our data. Variant chr5-147828151-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239508.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 = 0.00208 (316/152280) while in subpopulation NFE AF = 0.00378 (257/68006). AF 95% confidence interval is 0.0034. There are 0 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 316 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379610.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPINK1	NM_001379610.1	MANE Select	c.88-23A>T	intron	N/A	NP_001366539.1	P00995
SPINK1	NM_001354966.2		c.88-23A>T	intron	N/A	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.88-23A>T	intron	N/A	NP_003113.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.88-23A>T	intron	N/A	ENSP00000296695.5	P00995
SPINK1	ENST00000510027.2	TSL:3	c.88-23A>T	intron	N/A	ENSP00000427376.1	D6RIU5
SPINK1	ENST00000505722.1	TSL:2	n.-21A>T	upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

316

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00246

AC:

590

AN:

239486

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.000319

Gnomad AMR exome

AF:

0.00106

Gnomad ASJ exome

AF:

0.00296

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000935

Gnomad NFE exome

AF:

0.00451

Gnomad OTH exome

AF:

0.00270

GnomAD4 exome

AF:

0.00280

AC:

3945

AN:

1409298

Hom.:

Cov.:

AF XY:

0.00280

AC XY:

1970

AN XY:

703776

show subpopulations

African (AFR)

AF:

0.000432

AC:

AN:

32390

American (AMR)

AF:

0.00104

AC:

AN:

44326

Ashkenazi Jewish (ASJ)

AF:

0.00249

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

39154

South Asian (SAS)

AF:

0.0000592

AC:

AN:

84466

European-Finnish (FIN)

AF:

0.00135

AC:

AN:

51886

Middle Eastern (MID)

AF:

0.00106

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00339

AC:

3619

AN:

1067126

Other (OTH)

AF:

0.00207

AC:

121

AN:

58568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

191

381

572

762

953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.00208

AC:

316

AN:

152280

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41556

American (AMR)

AF:

0.00163

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00378

AC:

257

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.00237

Hom.:

Bravo

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary pancreatitis (4)

not provided (3)

Hereditary pancreatitis;C1842402:Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

0.92

La Branchor

0.60

BranchPoint Hunter

0.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over