rs1800209

Positions:

chr13-77000848-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 (★★).

Frequency

Genomes: 𝑓 0.19 ( 4375 hom., cov: 32)

Exomes 𝑓: 0.095 ( 10044 hom. )

Consequence

CLN5
NM_006493.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 3.82

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:

ENSG00000283208 (HGNC:):

ENSG00000283208 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CLN5	NM_006493.4 linkuse as main transcript	c.956A>G	p.Lys319Arg	missense_variant	4/4	ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 linkuse as main transcript	c.*405A>G		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 linkuse as main transcript	c.956A>G	p.Lys319Arg	missense_variant	4/4	1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 linkuse as main transcript	c.565+4721A>G		intron_variant		5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.190

AC:

28876

AN:

152026

Hom.:

4360

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0927

AC XY:

66897

AN XY:

721282

show subpopulations

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.:

AF XY:

0.191

AC XY:

14213

AN XY:

74412

show subpopulations

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:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -
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. -

Neuronal ceroid lipofuscinosis 5

Benign:3

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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

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	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis

Benign:2

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

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

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.064

T;T

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.15

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.0

.;N

PrimateAI

Benign

0.30

REVEL

Benign

0.29

Polyphen

0.0

.;B

MPC

0.14

ClinPred

0.0011

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

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