rs114094661

chr5-147827838-A-T

Variant summary

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

The NM_001379610.1(SPINK1):c.194+184T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 526,370 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 32)
  • Exomes 𝑓: 0.013 (57 hom.)
• Consequence: SPINK1 NM_001379610.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.225

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: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-147827838-A-T is Benign according to our data. Variant chr5-147827838-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 239506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1588/152286) while in subpopulation NFE AF= 0.0172 (1172/68016). AF 95% confidence interval is 0.0164. There are 12 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1587 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK1	NM_001379610.1	c.194+184T>A		intron_variant		ENST00000296695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK1	ENST00000296695.10	c.194+184T>A		intron_variant		1	NM_001379610.1	P1
SPINK1	ENST00000510027.2	c.*180T>A		3_prime_UTR_variant	3/3	3
SPINK1	ENST00000505722.1	n.109+184T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1587 AN: 152168 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0130 AC: 4863 AN: 374084 Hom.: 57 Cov.: 4 AF XY: 0.0127 AC XY: 2519 AN XY: 197978

Gnomad4 AFR exome AF: 0.00376

Gnomad4 AMR exome AF: 0.00658

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00476

Gnomad4 FIN exome AF: 0.00661

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0138

GnomAD4 genome AF: 0.0104 AC: 1588 AN: 152286 Hom.: 12 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74472

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0172

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0156 Hom.: 4

Bravo AF: 0.00971

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pancreatitis Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 05, 2024	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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2018

This variant is associated with the following publications: (PMID: 10982753, 28472998) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.64
Dann	Benign	0.65

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: rs114094661; hg19: chr5-147207401;