5-147828042-G-T

Variant names:

• chr5-147828042-G-T
• rs35737774
• NM_001379610.1:c.174C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PS3 PM2 PP5_Moderate

The NM_001379610.1(SPINK1):​c.174C>A​(p.Cys58*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002716118: This alteration results in the truncation at the amino acid residue 35 of the processed and mature SPINK1, a single protein domain consisting of 56 amino acid residues, and is anticipated to result in a significant decrease in structural stability (Horii A et al. Biochem. Biophys. Res. Commun. 1987 Dec" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. C58C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPINK1 NM_001379610.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0340
• Publications: 1 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, MODERATE, SUPPORTIVE, NO_KNOWN Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.275 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002716118: This alteration results in the truncation at the amino acid residue 35 of the processed and mature SPINK1, a single protein domain consisting of 56 amino acid residues, and is anticipated to result in a significant decrease in structural stability (Horii A et al. Biochem. Biophys. Res. Commun. 1987 Dec; 149(2):635-41; Hecht HJ et al. J. Mol. Biol. 1991 Aug; 220(3):711-22; Hecht HJ et al. J. Mol. Biol. 1992 Jun; 225(4):1095-103).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-147828042-G-T is Pathogenic according to our data. Variant chr5-147828042-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1779356.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	NM_001379610.1	MANE Select	c.174C>A	p.Cys58*	stop_gained	Exon 3 of 4	NP_001366539.1	P00995
	SPINK1	NM_001354966.2		c.174C>A	p.Cys58*	stop_gained	Exon 4 of 5	NP_001341895.1	P00995
	SPINK1	NM_003122.5		c.174C>A	p.Cys58*	stop_gained	Exon 4 of 5	NP_003113.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPINK1	ENST00000296695.10	TSL:1 MANE Select	c.174C>A	p.Cys58*	stop_gained	Exon 3 of 4	ENSP00000296695.5	P00995
	SPINK1	ENST00000510027.2	TSL:3	c.174C>A	p.Cys58*	stop_gained	Exon 3 of 3	ENSP00000427376.1	D6RIU5
	SPINK1	ENST00000505722.1	TSL:2	n.89C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460562 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726656

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111386

Other (OTH) AF: 0.00 AC: 0 AN: 60342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Benign	0.96
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.12	N
PhyloP100		-0.034
Vest4		0.95
GERP RS		-1.0
Mutation Taster		=67/133	disease causing

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: rs35737774; hg19: chr5-147207605;