rs779832256

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_003122.5(SPINK1):c.-147A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,513,248 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00062 ( 6 hom. )

Consequence

SPINK1
NM_003122.5 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2O:1

Conservation

PhyloP100: 3.28

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

SPINK1 links:

LOC124901101 (HGNC:):

LOC124901101 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003122.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000742 (113/152332) while in subpopulation NFE AF = 0.000309 (21/68036). AF 95% confidence interval is 0.000207. There are 2 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 113 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003122.5. 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_001354966.2		c.-147A>G	5_prime_UTR	Exon 2 of 5	NP_001341895.1	P00995
SPINK1	NM_003122.5		c.-147A>G	5_prime_UTR	Exon 2 of 5	NP_003113.2
SPINK1	NM_001379610.1	MANE Select	c.-147A>G	upstream_gene	N/A	NP_001366539.1	P00995

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.-147A>G		upstream_gene	N/A	ENSP00000296695.5	P00995
	SPINK1	ENST00000510027.2	TSL:3	c.-147A>G		upstream_gene	N/A	ENSP00000427376.1	D6RIU5

Frequencies

GnomAD3 genomes

AF:

0.000749

AC:

114

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.000619

AC:

843

AN:

1360916

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

446

AN XY:

670008

show subpopulations

African (AFR)

AF:

0.000195

AC:

AN:

30714

American (AMR)

AF:

0.000472

AC:

AN:

33918

Ashkenazi Jewish (ASJ)

AF:

0.0214

AC:

509

AN:

23738

East Asian (EAS)

AF:

0.00

AC:

AN:

35166

South Asian (SAS)

AF:

0.000196

AC:

AN:

76388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34678

Middle Eastern (MID)

AF:

0.00765

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

0.000165

AC:

176

AN:

1065740

Other (OTH)

AF:

0.00159

AC:

AN:

56522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152332

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41570

American (AMR)

AF:

0.000196

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68036

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000763

Hom.:

Bravo

AF:

0.000733

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hereditary pancreatitis (3)

Hereditary pancreatitis;C1842402:Tropical pancreatitis (1)

SPINK1-related disorder (1)

Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.69

PhyloP100

3.3

PromoterAI

-0.21

Neutral

(source)

Mutation Taster

=298/2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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