rs779832256

Variant names:

• chr5-147831724-T-C
• rs779832256
• NM_001354966.2:c.-147A>G

Variant summary

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

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2 O:1
• Conservation: PhyloP100: 3.28
• 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=-0.53).
• 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. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	NM_001354966.2		c.-147A>G		5_prime_UTR	Exon 2 of 5	NP_001341895.1
	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

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
	SPINK1	ENST00000510027.2	TSL:3	c.-147A>G		upstream_gene	N/A	ENSP00000427376.1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152214 Hom.: 2 Cov.: 33

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.: 6 Cov.: 30 AF XY: 0.000666 AC XY: 446 AN XY: 670008

African (AFR) AF: 0.000195 AC: 6 AN: 30714

American (AMR) AF: 0.000472 AC: 16 AN: 33918

Ashkenazi Jewish (ASJ) AF: 0.0214 AC: 509 AN: 23738

East Asian (EAS) AF: 0.00 AC: 0 AN: 35166

South Asian (SAS) AF: 0.000196 AC: 15 AN: 76388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34678

Middle Eastern (MID) AF: 0.00765 AC: 31 AN: 4052

European-Non Finnish (NFE) AF: 0.000165 AC: 176 AN: 1065740

Other (OTH) AF: 0.00159 AC: 90 AN: 56522

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152332 Hom.: 2 Cov.: 33 AF XY: 0.000631 AC XY: 47 AN XY: 74490

African (AFR) AF: 0.000241 AC: 10 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68036

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.000733

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.69
PhyloP100		3.3
PromoterAI		-0.21	Neutral
Mutation Taster		=298/2	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: rs779832256; hg19: chr5-147211287;