13-76991958-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000636183.2(CLN5):​c.-141C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000816 in 1,568,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

CLN5
ENST00000636183.2 5_prime_UTR

Scores

1
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: -4.23
Variant links:
Genes affected
CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08296952).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLN5ENST00000636183.2 linkuse as main transcriptc.-141C>T 5_prime_UTR_variant 1/41 ENSP00000490181 P1

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000360
AC:
6
AN:
166574
Hom.:
0
AF XY:
0.0000324
AC XY:
3
AN XY:
92630
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000854
AC:
121
AN:
1416140
Hom.:
0
Cov.:
34
AF XY:
0.0000727
AC XY:
51
AN XY:
701738
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.000108
Gnomad4 OTH exome
AF:
0.0000509
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000109
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000352
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:2
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Nov 19, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 06, 2022This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3 of the CLN5 protein (p.Arg3Trp). This variant is present in population databases (rs759859373, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 205135). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -
Neuronal ceroid lipofuscinosis 5 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMay 18, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.47
DANN
Benign
0.94
DEOGEN2
Benign
0.068
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.012
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.00052
T
MetaRNN
Benign
0.083
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.55
T
MutPred
0.38
Gain of catalytic residue at G8 (P = 0);
ClinPred
0.24
T
GERP RS
-6.3

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: rs759859373; hg19: chr13-77566093; API