rs28940280

Positions:

• chr13-77000580-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_006493.4(CLN5):​c.688G>A​(p.Asp230Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-77000580-G-A is Pathogenic according to our data. Variant chr13-77000580-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2566.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=1}. Variant chr13-77000580-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN5	NM_006493.4	c.688G>A	p.Asp230Asn	missense_variant	4/4	ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.*137G>A		3_prime_UTR_variant	5/5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.688G>A	p.Asp230Asn	missense_variant	4/4	1	NM_006493.4	ENSP00000366673	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251366 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461848 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000997 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -

Neuronal ceroid lipofuscinosis Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 279 of the CLN5 protein (p.Asp279Asn). This variant is present in population databases (rs28940280, gnomAD 0.006%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9662406, 16814585). ClinVar contains an entry for this variant (Variation ID: 2566). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CLN5 function (PMID: 12134079, 20052765, 24058541, 26342652). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 23, 2024

Variant summary: CLN5 c.688G>A (p.Asp230Asn), also reported as "c.835G>A (D279N)" results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251366 control chromosomes. c.688G>A has been reported individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Bessa_2006, Savukoski_1998). These data indicate that the variant may be associated with disease. Multiple in vitro studies demonstrated variant impacts glycosylation, maturation, and localization of the protein (example, DeSilva_2015, Moharir_2013, Schmiedt_2010). The following publications have been ascertained in the context of this evaluation (PMID: 16814585, 26342652, 24058541, 9662406, 20052765). ClinVar contains an entry for this variant (Variation ID: 2566). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.51	T
REVEL	Uncertain	0.54
Polyphen		1.0	.;D
MutPred		0.57		.;Gain of MoRF binding (P = 0.0806);
MVP		0.99
MPC		0.72
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.30

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: rs28940280; hg19: chr13-77574715; COSMIC: COSV100842302; COSMIC: COSV100842302;