1-15461640-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS2_Supporting
The NM_033440.3(CELA2A):c.209C>T(p.Thr70Met) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,696 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 2 hom. )
Consequence
CELA2A
NM_033440.3 missense
NM_033440.3 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 5.79
Genes affected
CELA2A (HGNC:24609): (chymotrypsin like elastase 2A) Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes which encode the structurally similar proteins elastase 1, 2, 2A, 2B, 3A, and 3B. Like most of the human elastases, elastase 2A is secreted from the pancreas as a zymogen. In other species, elastase 2A has been shown to preferentially cleave proteins after leucine, methionine, and phenylalanine residues. [provided by RefSeq, May 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.923
PP5
Variant 1-15461640-C-T is Pathogenic according to our data. Variant chr1-15461640-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 633595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 17 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CELA2A | NM_033440.3 | c.209C>T | p.Thr70Met | missense_variant | 3/8 | ENST00000359621.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CELA2A | ENST00000359621.5 | c.209C>T | p.Thr70Met | missense_variant | 3/8 | 1 | NM_033440.3 | P1 | |
CELA2A | ENST00000459653.1 | n.235C>T | non_coding_transcript_exon_variant | 3/4 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000211 AC: 53AN: 251464Hom.: 0 AF XY: 0.000272 AC XY: 37AN XY: 135908
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GnomAD4 exome AF: 0.000109 AC: 160AN: 1461334Hom.: 2 Cov.: 31 AF XY: 0.000140 AC XY: 102AN XY: 726996
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GnomAD4 genome AF: 0.000112 AC: 17AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74496
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Abdominal obesity-metabolic syndrome 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | - - |
Hypertensive disorder;C0813230:Hypertriglyceridemia;C1320657:Diabetes;C1956346:Coronary artery disorder Pathogenic:1
Pathogenic, no assertion criteria provided | research | Mani Lab, Yale Cardiovascular Research Center, Yale University | Jan 01, 2017 | - - |
CELA2A-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 29, 2024 | The CELA2A c.209C>T variant is predicted to result in the amino acid substitution p.Thr70Met. This variant has been reported in an individual with early-onset coronary artery disease (Esteghamat F et al. 2019. PubMed ID: 31358993). In vitro functional studies show this variant impacts protein function (Esteghamat F et al. 2019. PubMed ID: 31358993). This variant is reported in 0.11% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at