chr2-44332605-T-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_001171613.2(PREPL):​c.940A>T​(p.Asn314Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000331 in 1,613,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

PREPL
NM_001171613.2 missense

Scores

7
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.60
Variant links:
Genes affected
PREPL (HGNC:30228): (prolyl endopeptidase like) The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.[provided by RefSeq, Jan 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.012288243).
BP6
Variant 2-44332605-T-A is Benign according to our data. Variant chr2-44332605-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 436416.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0017 (259/152306) while in subpopulation AFR AF= 0.00585 (243/41560). AF 95% confidence interval is 0.00524. There are 0 homozygotes in gnomad4. There are 133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes 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 rank MANE Protein UniProt
PREPLNM_001171613.2 linkc.940A>T p.Asn314Tyr missense_variant Exon 8 of 14 ENST00000409411.6 NP_001165084.1 Q4J6C6-4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PREPLENST00000409411.6 linkc.940A>T p.Asn314Tyr missense_variant Exon 8 of 14 1 NM_001171613.2 ENSP00000387095.2 Q4J6C6-4

Frequencies

GnomAD3 genomes
AF:
0.00171
AC:
260
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00589
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000589
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.000462
AC:
116
AN:
251316
Hom.:
1
AF XY:
0.000331
AC XY:
45
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.00603
Gnomad AMR exome
AF:
0.000347
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000188
AC:
275
AN:
1461670
Hom.:
2
Cov.:
30
AF XY:
0.000169
AC XY:
123
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.00583
Gnomad4 AMR exome
AF:
0.000313
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000131
Gnomad4 NFE exome
AF:
0.0000297
Gnomad4 OTH exome
AF:
0.000381
GnomAD4 genome
AF:
0.00170
AC:
259
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.00179
AC XY:
133
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00585
Gnomad4 AMR
AF:
0.000588
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00236
Alfa
AF:
0.000692
Hom.:
0
Bravo
AF:
0.00194
ESP6500AA
AF:
0.00658
AC:
29
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000568
AC:
69
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 13, 2016- -
Myasthenic syndrome, congenital, 22 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 23, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.011
.;.;.;T;T;T;T;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.81
T;.;.;.;.;.;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.012
T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
.;.;.;N;N;N;N;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.98
N;N;N;N;N;N;N;N
REVEL
Benign
0.15
Sift
Uncertain
0.024
D;D;D;D;D;D;D;T
Sift4G
Uncertain
0.012
D;D;D;D;D;D;D;D
Polyphen
0.98, 0.98
.;.;.;D;D;D;D;D
Vest4
0.61
MVP
0.63
MPC
0.014
ClinPred
0.040
T
GERP RS
4.7
Varity_R
0.091
gMVP
0.54

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: rs140990611; hg19: chr2-44559744; API