rs1800209

Positions:

• chr13-77000848-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006493.4(CLN5):​c.956A>G​(p.Lys319Arg) variant causes a missense change. The variant allele was found at a frequency of 0.104 in 1,603,422 control chromosomes in the GnomAD database, including 14,419 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K319E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.19 (4375 hom., cov: 32)
  • Exomes 𝑓: 0.095 (10044 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 3.82

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035348833).
• BP6: Variant 13-77000848-A-G is Benign according to our data. Variant chr13-77000848-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-77000848-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4	c.956A>G	p.Lys319Arg	missense_variant	4/4	ENST00000377453.9
CLN5	NM_001366624.2	c.*405A>G		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.956A>G	p.Lys319Arg	missense_variant	4/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28876 AN: 152026 Hom.: 4360 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.270

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.0743

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.141 AC: 34273 AN: 242548 Hom.: 3656 AF XY: 0.128 AC XY: 16772 AN XY: 130972

Gnomad AFR exome AF: 0.415

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.0982

Gnomad EAS exome AF: 0.262

Gnomad SAS exome AF: 0.0898

Gnomad FIN exome AF: 0.0926

Gnomad NFE exome AF: 0.0790

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.0947 AC: 137381 AN: 1451278 Hom.: 10044 Cov.: 33 AF XY: 0.0927 AC XY: 66897 AN XY: 721282

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.0949

Gnomad4 EAS exome AF: 0.271

Gnomad4 SAS exome AF: 0.0893

Gnomad4 FIN exome AF: 0.0965

Gnomad4 NFE exome AF: 0.0719

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.190 AC: 28943 AN: 152144 Hom.: 4375 Cov.: 32 AF XY: 0.191 AC XY: 14213 AN XY: 74412

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.270

Gnomad4 SAS AF: 0.0926

Gnomad4 FIN AF: 0.0920

Gnomad4 NFE AF: 0.0743

Gnomad4 OTH AF: 0.164

Alfa AF: 0.104 Hom.: 2110

Bravo AF: 0.210

TwinsUK AF: 0.0744 AC: 276

ALSPAC AF: 0.0688 AC: 265

ESP6500AA AF: 0.402 AC: 1771

ESP6500EA AF: 0.0787 AC: 676

ExAC AF: 0.141 AC: 17061

Asia WGS AF: 0.202 AC: 702 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 23. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Neuronal ceroid lipofuscinosis 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Neuronal ceroid lipofuscinosis Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 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, Dominant/Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.78
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.15	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
Polyphen		0.0	.;B
MPC		0.14
ClinPred		0.0011	T
GERP RS		5.0
Varity_R		0.057

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: rs1800209; hg19: chr13-77574983; COSMIC: COSV62918786; COSMIC: COSV62918786;