chr5-147831719-A-G

Variant names:

• chr5-147831719-A-G
• rs755968566
• NM_001354966.2:c.-142T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001354966.2(SPINK1):​c.-142T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,516,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SPINK1 NM_001354966.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.42
• Publications: 4 publications found

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

LOC124901101 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000158 (24/152334) while in subpopulation NFE AF = 0.000279 (19/68034). AF 95% confidence interval is 0.000182. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 24 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001354966.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	NM_001354966.2		c.-142T>C		5_prime_UTR	Exon 2 of 5	NP_001341895.1
	SPINK1	NM_003122.5		c.-142T>C		5_prime_UTR	Exon 2 of 5	NP_003113.2
	SPINK1	NM_001379610.1	MANE Select	c.-142T>C		upstream_gene	N/A	NP_001366539.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.-142T>C		upstream_gene	N/A	ENSP00000296695.5
	SPINK1	ENST00000510027.2	TSL:3	c.-142T>C		upstream_gene	N/A	ENSP00000427376.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000185 AC: 252 AN: 1364074 Hom.: 0 Cov.: 30 AF XY: 0.000185 AC XY: 124 AN XY: 671976

African (AFR) AF: 0.00 AC: 0 AN: 30788

American (AMR) AF: 0.000322 AC: 11 AN: 34142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23934

East Asian (EAS) AF: 0.00 AC: 0 AN: 35192

South Asian (SAS) AF: 0.0000779 AC: 6 AN: 76986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35134

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4142

European-Non Finnish (NFE) AF: 0.000206 AC: 220 AN: 1067126

Other (OTH) AF: 0.000159 AC: 9 AN: 56630

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74490

African (AFR) AF: 0.0000240 AC: 1 AN: 41580

American (AMR) AF: 0.000261 AC: 4 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000347 Hom.: 0

Bravo AF: 0.000234

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary pancreatitis (3)
-	1	-	Hereditary pancreatitis;C1842402:Tropical pancreatitis (1)
-	1	-	not provided (1)
-	1	-	SPINK1-related disorder (1)
-	1	-	Tropical pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.78
PhyloP100		2.4
PromoterAI		-0.15	Neutral
Mutation Taster		=297/3	polymorphism

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

Other links and lift over

dbSNP: rs755968566; hg19: chr5-147211282;