1-15461640-C-T

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

Scores

13
5
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.79
Variant links:
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]

Genome browser will be placed here

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
CELA2ANM_033440.3 linkuse as main transcriptc.209C>T p.Thr70Met missense_variant 3/8 ENST00000359621.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CELA2AENST00000359621.5 linkuse as main transcriptc.209C>T p.Thr70Met missense_variant 3/81 NM_033440.3 P1
CELA2AENST00000459653.1 linkuse as main transcriptn.235C>T non_coding_transcript_exon_variant 3/42

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152244
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000769
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
251464
Hom.:
0
AF XY:
0.000272
AC XY:
37
AN XY:
135908
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000979
Gnomad SAS exome
AF:
0.00101
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000109
AC:
160
AN:
1461334
Hom.:
2
Cov.:
31
AF XY:
0.000140
AC XY:
102
AN XY:
726996
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000378
Gnomad4 SAS exome
AF:
0.00104
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000414
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.000112
AC:
17
AN:
152362
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000771
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000642
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000222
AC:
27

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 submitterclinical testingMendelicsMay 04, 2022- -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-- -
Hypertensive disorder;C0813230:Hypertriglyceridemia;C1320657:Diabetes;C1956346:Coronary artery disorder Pathogenic:1
Pathogenic, no assertion criteria providedresearchMani Lab, Yale Cardiovascular Research Center, Yale UniversityJan 01, 2017- -
CELA2A-related disorder Pathogenic:1
Likely pathogenic, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 29, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.86
D
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
5.0
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-5.7
D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.92
MVP
0.91
MPC
1.1
ClinPred
0.91
D
GERP RS
3.3
Varity_R
0.80
gMVP
0.94

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372947070; hg19: chr1-15788135; COSMIC: COSV62747322; COSMIC: COSV62747322; API