chr13-76995076-C-T

Position:

• chr13-76995076-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_006493.4(CLN5):​c.187C>T​(p.Arg63Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R63P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 6.04

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-76995077-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• PP5: Variant 13-76995076-C-T is Pathogenic according to our data. Variant chr13-76995076-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190222.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4	c.187C>T	p.Arg63Cys	missense_variant	2/4	ENST00000377453.9
CLN5	NM_001366624.2	c.187C>T	p.Arg63Cys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.187C>T	p.Arg63Cys	missense_variant	2/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726904

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5 Pathogenic:2 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 16, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Mendelics	Feb 14, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Neuronal ceroid lipofuscinosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 112 of the CLN5 protein (p.Arg112Cys). This variant is present in population databases (rs786205211, gnomAD 0.007%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (PMID: 30078242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190222). 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 expected to disrupt CLN5 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15728307, 20052765, 30078242). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2018

The p.R112C variant (also known as c.334C>T), located in coding exon 2 of the CLN5 gene, results from a C to T substitution at nucleotide position 334. The arginine at codon 112 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;T;D;T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D;.;.;.
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.4	.;.;M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	.;.;N;.;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.019	.;.;D;.;.;.
Polyphen		1.0	.;.;D;.;.;.
MutPred		0.70		.;.;Loss of disorder (P = 0.0215);.;.;.;
MVP		0.99
MPC		0.85
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.64

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

Other links and lift over

dbSNP: rs786205211; hg19: chr13-77569211;