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GeneBe

13-76991955-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000636183.2(CLN5):c.-144C>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 0.122 in 1,563,562 control chromosomes in the GnomAD database, including 12,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 1362 hom., cov: 33)
Exomes 𝑓: 0.12 ( 11016 hom. )

Consequence

CLN5
ENST00000636183.2 5_prime_UTR

Scores

2
10

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.316
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004951477).
BP6
Variant 13-76991955-C-T is Benign according to our data. Variant chr13-76991955-C-T is described in ClinVar as [Benign]. Clinvar id is 128782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-76991955-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLN5ENST00000636183.2 linkuse as main transcriptc.-144C>T 5_prime_UTR_variant 1/41 P1

Frequencies

GnomAD3 genomes
AF:
0.128
AC:
19446
AN:
152048
Hom.:
1361
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.137
Gnomad AMI
AF:
0.0418
Gnomad AMR
AF:
0.207
Gnomad ASJ
AF:
0.0887
Gnomad EAS
AF:
0.122
Gnomad SAS
AF:
0.126
Gnomad FIN
AF:
0.109
Gnomad MID
AF:
0.111
Gnomad NFE
AF:
0.112
Gnomad OTH
AF:
0.116
GnomAD3 exomes
AF:
0.145
AC:
23394
AN:
160952
Hom.:
2043
AF XY:
0.139
AC XY:
12423
AN XY:
89384
show subpopulations
Gnomad AFR exome
AF:
0.150
Gnomad AMR exome
AF:
0.280
Gnomad ASJ exome
AF:
0.0942
Gnomad EAS exome
AF:
0.113
Gnomad SAS exome
AF:
0.131
Gnomad FIN exome
AF:
0.103
Gnomad NFE exome
AF:
0.113
Gnomad OTH exome
AF:
0.139
GnomAD4 exome
AF:
0.121
AC:
171247
AN:
1411396
Hom.:
11016
Cov.:
35
AF XY:
0.121
AC XY:
84441
AN XY:
699018
show subpopulations
Gnomad4 AFR exome
AF:
0.142
Gnomad4 AMR exome
AF:
0.272
Gnomad4 ASJ exome
AF:
0.0913
Gnomad4 EAS exome
AF:
0.111
Gnomad4 SAS exome
AF:
0.130
Gnomad4 FIN exome
AF:
0.102
Gnomad4 NFE exome
AF:
0.117
Gnomad4 OTH exome
AF:
0.120
GnomAD4 genome
AF:
0.128
AC:
19457
AN:
152166
Hom.:
1362
Cov.:
33
AF XY:
0.128
AC XY:
9498
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.137
Gnomad4 AMR
AF:
0.207
Gnomad4 ASJ
AF:
0.0887
Gnomad4 EAS
AF:
0.121
Gnomad4 SAS
AF:
0.126
Gnomad4 FIN
AF:
0.109
Gnomad4 NFE
AF:
0.112
Gnomad4 OTH
AF:
0.114
Alfa
AF:
0.112
Hom.:
1192
Bravo
AF:
0.136
TwinsUK
AF:
0.112
AC:
416
ALSPAC
AF:
0.118
AC:
455
ESP6500AA
AF:
0.113
AC:
400
ESP6500EA
AF:
0.101
AC:
731
ExAC
AF:
0.106
AC:
11817
Asia WGS
AF:
0.111
AC:
386
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 13, 2016- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Neuronal ceroid lipofuscinosis 5 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 10, 2021- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 30919163) -
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicDec 15, 2015- -
Neuronal ceroid lipofuscinosis Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 08, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.67
T
BayesDel_noAF
Benign
-0.60
Cadd
Benign
13
Dann
Uncertain
0.98
DEOGEN2
Benign
0.067
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.69
FATHMM_MKL
Benign
0.075
N
LIST_S2
Benign
0.41
T
MetaRNN
Benign
0.0050
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
P
PrimateAI
Uncertain
0.58
T
ClinPred
0.099
T
GERP RS
2.1

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: rs77416795; hg19: chr13-77566090; COSMIC: COSV66283779; COSMIC: COSV66283779; API