chr20-45890594-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080749.4(NEURL2):​c.398C>T​(p.Ala133Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,459,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NEURL2
NM_080749.4 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.64
Variant links:
Genes affected
NEURL2 (HGNC:16156): (neuralized E3 ubiquitin protein ligase 2) This gene encodes a protein that is involved in the regulation of myofibril organization. This protein is likely the adaptor component of the E3 ubiquitin ligase complex in striated muscle, and it regulates the ubiquitin-mediated degradation of beta-catenin during myogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2013]
CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.042953134).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NEURL2NM_080749.4 linkuse as main transcriptc.398C>T p.Ala133Val missense_variant 1/2 ENST00000372518.5
NEURL2NM_001278535.2 linkuse as main transcriptc.398C>T p.Ala133Val missense_variant 1/2
SPATA25XM_024451826.2 linkuse as main transcriptc.-2166C>T 5_prime_UTR_variant 1/3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NEURL2ENST00000372518.5 linkuse as main transcriptc.398C>T p.Ala133Val missense_variant 1/21 NM_080749.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000123
AC:
3
AN:
244300
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133442
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000874
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1459972
Hom.:
0
Cov.:
37
AF XY:
0.00000688
AC XY:
5
AN XY:
726222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 15, 2024The c.398C>T (p.A133V) alteration is located in exon 1 (coding exon 1) of the NEURL2 gene. This alteration results from a C to T substitution at nucleotide position 398, causing the alanine (A) at amino acid position 133 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.075
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.72
CADD
Benign
6.4
DANN
Benign
0.94
DEOGEN2
Benign
0.021
T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.035
N
LIST_S2
Benign
0.54
T
M_CAP
Benign
0.0056
T
MetaRNN
Benign
0.043
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.83
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.40
T
PROVEAN
Benign
0.050
N
REVEL
Benign
0.0050
Sift
Benign
0.39
T
Sift4G
Benign
0.31
T
Polyphen
0.0
B
Vest4
0.13
MutPred
0.24
Gain of sheet (P = 0.0073);
MVP
0.061
MPC
0.70
ClinPred
0.042
T
GERP RS
-7.7
Varity_R
0.032
gMVP
0.44

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: rs773310703; hg19: chr20-44519233; API