rs138611001

chr13-77000471-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006493.4(CLN5):c.579C>A(p.Asn193Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,611,868 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0090 (8 hom., cov: 32)
  • Exomes 𝑓: 0.014 (160 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: 0.522

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009227604).
• BP6: Variant 13-77000471-C-A is Benign according to our data. Variant chr13-77000471-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136794.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Uncertain_significance=1, Likely_benign=1}. Variant chr13-77000471-C-A is described in Lovd as [Likely_benign]. Variant chr13-77000471-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00897 (1357/151204) while in subpopulation NFE AF= 0.0153 (1037/67890). AF 95% confidence interval is 0.0145. There are 8 homozygotes in gnomad4. There are 613 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4	c.579C>A	p.Asn193Lys	missense_variant	4/4	ENST00000377453.9
CLN5	NM_001366624.2	c.*28C>A		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.579C>A	p.Asn193Lys	missense_variant	4/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1357 AN: 151112 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00422

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0107

Gnomad FIN AF: 0.00605

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.00719

GnomAD3 exomes AF: 0.00933 AC: 2333 AN: 250114 Hom.: 24 AF XY: 0.00983 AC XY: 1330 AN XY: 135276

Gnomad AFR exome AF: 0.00294

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00967

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.00788

GnomAD4 exome AF: 0.0137 AC: 20037 AN: 1460664 Hom.: 160 Cov.: 33 AF XY: 0.0136 AC XY: 9916 AN XY: 726486

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00415

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0104

Gnomad4 FIN exome AF: 0.00560

Gnomad4 NFE exome AF: 0.0159

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.00897 AC: 1357 AN: 151204 Hom.: 8 Cov.: 32 AF XY: 0.00831 AC XY: 613 AN XY: 73772

Gnomad4 AFR AF: 0.00262

Gnomad4 AMR AF: 0.00421

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0107

Gnomad4 FIN AF: 0.00605

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.00713

Alfa AF: 0.0135 Hom.: 17

Bravo AF: 0.00836

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.00965 AC: 1172

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0120

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5 Uncertain:1 Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 19, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Benign, for Ceroid lipofuscinosis, neuronal, 5, autosomal recessive. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 27, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not provided Uncertain:1 Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	This variant is associated with the following publications: (PMID: 24767253, 21990111) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CLN5: BS1, BS2 -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 14, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neuronal ceroid lipofuscinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;D
Eigen	Benign	-0.0020
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.91	D;D
MetaRNN	Benign	0.0092	T;T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
Polyphen		1.0	.;D
MutPred		0.66		.;Gain of methylation at N193 (P = 0.0039);
MVP		0.97
MPC		0.78
ClinPred		0.029	T
GERP RS		4.1
Varity_R		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs138611001; hg19: chr13-77574606; COSMIC: COSV99053054; COSMIC: COSV99053054;