13-76995064-C-T

Position:

chr13-76995064-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006493.4(CLN5):c.175C>T(p.Arg59Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000616 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CLN5
NM_006493.4 missense, splice_region

Scores

Splicing: ADA: 0.9763

Clinical Significance

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

Conservation

PhyloP100: 6.00

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:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4 linkuse as main transcript	c.175C>T	p.Arg59Cys	missense_variant, splice_region_variant	2/4	ENST00000377453.9
CLN5	NM_001366624.2 linkuse as main transcript	c.175C>T	p.Arg59Cys	missense_variant, splice_region_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9 linkuse as main transcript	c.175C>T	p.Arg59Cys	missense_variant, splice_region_variant	2/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250754

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135508

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726754

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:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 108 of the CLN5 protein (p.Arg108Cys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 451777). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 10, 2020	- -

Neuronal ceroid lipofuscinosis 5

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2017

A variant of uncertain significance has been identified in the CLN5 gene. The R108C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R108C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R108C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;T;D;T;T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;.;D;.;.;.

M_CAP

Uncertain

0.28

MetaRNN

Pathogenic

0.79

D;D;D;D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.4

.;.;M;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.83

REVEL

Pathogenic

0.69

Polyphen

1.0

.;.;D;.;.;.

MutPred

0.54

.;.;Loss of MoRF binding (P = 0.0146);.;.;.;

MVP

0.99

MPC

0.85

ClinPred

1.0

GERP RS

5.8

Varity_R

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.87

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over