5-147828084-G-GTCA

Position:

• chr5-147828084-G-GTCA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001379610.1(SPINK1):​c.129_131dupTGA​(p.Asp44dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPINK1 NM_001379610.1 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001379610.1. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.129_131dupTGA	p.Asp44dup	disruptive_inframe_insertion	3/4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.129_131dupTGA	p.Asp44dup	disruptive_inframe_insertion	3/4	1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000510027.2	c.129_131dupTGA	p.Asp44dup	disruptive_inframe_insertion	3/3	3		ENSP00000427376.1
SPINK1	ENST00000505722.1	n.44_46dupTGA		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2018

This variant, c.129_131dupTGA, results in the insertion of 1 amino acid to the SPINK1 protein (p.Asp44dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SPINK1-related disease. ClinVar contains an entry for this variant (Variation ID: 239505). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the duplicated amino acid is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs878854607; hg19: chr5-147207647;