rs144656959

chr13-76996021-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BS1_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. 13/18 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9 B:2
• Conservation: PhyloP100: 3.37

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_006493.4
• PM2: Very rare variant in population databases, with high coverage
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4	c.459G>A	p.Met153Ile	missense_variant	3/4	ENST00000377453.9
CLN5	NM_001366624.2	c.459G>A	p.Met153Ile	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.459G>A	p.Met153Ile	missense_variant	3/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152198 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000553 AC: 139 AN: 251490 Hom.: 0 AF XY: 0.000581 AC XY: 79 AN XY: 135920

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 SAS 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.: 0 Cov.: 31 AF XY: 0.000958 AC XY: 697 AN XY: 727242

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74474

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000839 Hom.: 0

Bravo AF: 0.000608

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000763

EpiControl AF: 0.00113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 29, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	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 (Fernandez-Marmiesse et al., 2014).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24767253) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 12, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Neuronal ceroid lipofuscinosis 5 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 31, 2022

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	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	18
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	D
LIST_S2	Benign	0.72	T;.;T;.;.;.;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.037	T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.49	T
Polyphen		0.0040	.;.;B;.;.;.;.
MutPred		0.21		.;.;Gain of helix (P = 0.132);.;.;.;.;
MVP		0.83
MPC		0.24
ClinPred		0.015	T
GERP RS		3.8
Varity_R		0.090

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

LitVar

Other links and lift over

dbSNP: rs144656959; hg19: chr13-77570156;