chr13-76996021-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS1_Supporting

The NM_006493.4(CLN5):c.459G>A(p.Met153Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000921 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 0 hom. )

Consequence

CLN5
NM_006493.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9B:2

Conservation

PhyloP100: 3.37

Publications

7 publications found

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]

CLN5 links:

ENSG00000283208 (HGNC:):

ENSG00000283208 links:

FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

FBXL3 Gene-Disease associations (from GenCC):

intellectual disability, short stature, facial anomalies, and joint dislocations
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FBXL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_006493.4

BP4

Computational evidence support a benign effect (MetaRNN=0.03689459).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000584 (89/152316) while in subpopulation NFE AF = 0.00106 (72/68034). AF 95% confidence interval is 0.000861. There are 0 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4 link	c.459G>A	p.Met153Ile	missense_variant	Exon 3 of 4	ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 link	c.459G>A	p.Met153Ile	missense_variant	Exon 3 of 5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9 link	c.459G>A	p.Met153Ile	missense_variant	Exon 3 of 4	1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 link	c.459G>A	p.Met153Ile	missense_variant	Exon 3 of 5	5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000553

AC:

139

AN:

251490

AF XY:

0.000581

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000956

AC:

1398

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000958

AC XY:

697

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00117

AC:

1306

AN:

1111998

Other (OTH)

AF:

0.000911

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

156

234

312

390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000584

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41576

American (AMR)

AF:

0.000392

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

68034

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000855

Hom.:

Bravo

AF:

0.000608

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Aug 12, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 21, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in the heterozygous state in two unrelated individuals who were suspected to have a lysosomal storage disorder; a second CLN5 variant was not identified, and no additional information was provided (PMID: 24767253); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24767253) -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis 5

Uncertain:3

Apr 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 13, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.606G>A (p.M202I) alteration is located in exon 3 (coding exon 3) of the CLN5 gene. This alteration results from a G to A substitution at nucleotide position 606, causing the methionine (M) at amino acid position 202 to be replaced by an isoleucine (I). Based on data from the Genome Aggregation Database (gnomAD) database, the CLN5 c.606G>A alteration was observed in 0.05% (146/282884) of total alleles studied, with a frequency of 0.1% (126/129190) in the European (non-Finnish) subpopulation. This variant was identified in two individuals with a clinical suspicion of a lysosomal storage disease; however, no second CLN5 variants were identified (Fernández-Marmiesse, 2014). This amino acid position is not well conserved in available vertebrate species. The p.M202I alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis

Uncertain:1

Oct 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 202 of the CLN5 protein (p.Met202Ile). This variant is present in population databases (rs144656959, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with lysosomal storage disease (PMID: 24767253). ClinVar contains an entry for this variant (Variation ID: 205145). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN5 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

T;T;D;T;T;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.065

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

T;.;T;.;.;.;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.037

T;T;T;T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.8

.;.;L;.;.;.;.

PhyloP100

3.4

PrimateAI

Uncertain

0.49

REVEL

Benign

0.26

Polyphen

0.0040

.;.;B;.;.;.;.

MutPred

0.21

.;.;Gain of helix (P = 0.132);.;.;.;.;

MVP

0.83

MPC

0.24

ClinPred

0.015

GERP RS

3.8

PromoterAI

-0.040

Neutral

(source)

Varity_R

0.090

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr13-76996021-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over