chr5-147828151-T-A

Position:

• chr5-147828151-T-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000296695.10(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 ENST00000296695.10 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.915

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 0 / 10). 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 [Likely_benign]. Clinvar id is 239508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-147828151-T-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 316 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.88-23A>T		intron_variant		ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.88-23A>T		intron_variant		1	NM_001379610.1	ENSP00000296695	P1
SPINK1	ENST00000510027.2	c.88-23A>T		intron_variant		3		ENSP00000427376
SPINK1	ENST00000505722.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152162 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00246 AC: 590 AN: 239486 Hom.: 1 AF XY: 0.00256 AC XY: 331 AN XY: 129490

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 SAS exome AF: 0.000136

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.: 8 Cov.: 22 AF XY: 0.00280 AC XY: 1970 AN XY: 703776

Gnomad4 AFR exome AF: 0.000432

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00249

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000592

Gnomad4 FIN exome AF: 0.00135

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74472

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00378

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00237 Hom.: 0

Bravo AF: 0.00202

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 26, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 20, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 31, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 22, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary pancreatitis;C1842402:Tropical pancreatitis Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.64
La Branchor		0.60
BranchPoint Hunter		0.0

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

LitVar

Other links and lift over

dbSNP: rs199929811; hg19: chr5-147207714;