rs576564400
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000296695.10(SPINK1):c.206C>T(p.Thr69Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
ENST00000296695.10 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPINK1 | NM_001379610.1 | c.206C>T | p.Thr69Ile | missense_variant | 4/4 | ENST00000296695.10 | NP_001366539.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPINK1 | ENST00000296695.10 | c.206C>T | p.Thr69Ile | missense_variant | 4/4 | 1 | NM_001379610.1 | ENSP00000296695 | P1 | |
SPINK1 | ENST00000505722.1 | n.121C>T | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250498Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135424
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461754Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727182
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74440
ClinVar
Submissions by phenotype
Hereditary pancreatitis Pathogenic:1Uncertain:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2021 | The p.T69I variant (also known as c.206C>T), located in coding exon 4 of the SPINK1 gene, results from a C to T substitution at nucleotide position 206. The threonine at codon 69 is replaced by isoleucine, an amino acid with similar properties. This alteration was identified in multiple individuals with chronic pancreatitis (Rerknimitr R et al. JOP, 2008;9:33-6; Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204). This amino acid position is poorly conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2021 | This variant is present in population databases (rs576564400, ExAC 0.02%). This sequence change replaces threonine with isoleucine at codon 69 of the SPINK1 protein (p.Thr69Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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. Experimental studies have shown that this missense change abolishes SPINK1 protein expression in an overexpression system (PMID: 22343981). This variant has been observed in an individual affected with alcoholic pancreatitis (PMID: 18182741) and in individuals with idiopathic chronic pancreatitis (PMID: 30420730). ClinVar contains an entry for this variant (Variation ID: 440299). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 27, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at