13-76991955-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000636183.2(CLN5):c.-144C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,563,562 control chromosomes in the GnomAD database, including 12,378 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.13 ( 1362 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11016 hom. )

Consequence

CLN5
ENST00000636183.2 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.316

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

CLN5 links:

ENSG00000283208 (HGNC:):

ENSG00000283208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004951477).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4 link	c.-144C>T		upstream_gene_variant		ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 link	c.-144C>T		upstream_gene_variant			NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9 link	c.-144C>T		upstream_gene_variant		1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 link	c.-144C>T		upstream_gene_variant		5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

19446

AN:

152048

Hom.:

1361

Cov.:

show subpopulations

Gnomad AFR

AF:

0.137

Gnomad AMI

AF:

0.0418

Gnomad AMR

AF:

0.207

Gnomad ASJ

AF:

0.0887

Gnomad EAS

AF:

0.122

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.109

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.116

GnomAD2 exomes

AF:

0.145

AC:

23394

AN:

160952

AF XY:

0.139

show subpopulations

Gnomad AFR exome

AF:

0.150

Gnomad AMR exome

AF:

0.280

Gnomad ASJ exome

AF:

0.0942

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.103

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.139

GnomAD4 exome

AF:

0.121

AC:

171247

AN:

1411396

Hom.:

11016

Cov.:

AF XY:

0.121

AC XY:

84441

AN XY:

699018

show subpopulations

African (AFR)

AF:

0.142

AC:

4618

AN:

32530

American (AMR)

AF:

0.272

AC:

10487

AN:

38574

Ashkenazi Jewish (ASJ)

AF:

0.0913

AC:

2315

AN:

25360

East Asian (EAS)

AF:

0.111

AC:

4144

AN:

37184

South Asian (SAS)

AF:

0.130

AC:

10586

AN:

81484

European-Finnish (FIN)

AF:

0.102

AC:

4148

AN:

40574

Middle Eastern (MID)

AF:

0.112

AC:

629

AN:

5594

European-Non Finnish (NFE)

AF:

0.117

AC:

127258

AN:

1091356

Other (OTH)

AF:

0.120

AC:

7062

AN:

58740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

8562

17125

25687

34250

42812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.128

AC:

19457

AN:

152166

Hom.:

1362

Cov.:

AF XY:

0.128

AC XY:

9498

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.137

AC:

5672

AN:

41512

American (AMR)

AF:

0.207

AC:

3175

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0887

AC:

308

AN:

3472

East Asian (EAS)

AF:

0.121

AC:

628

AN:

5172

South Asian (SAS)

AF:

0.126

AC:

607

AN:

4824

European-Finnish (FIN)

AF:

0.109

AC:

1151

AN:

10598

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7608

AN:

67970

Other (OTH)

AF:

0.114

AC:

240

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

884

1768

2653

3537

4421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.114

Hom.:

1725

Bravo

AF:

0.136

TwinsUK

AF:

0.112

AC:

416

ALSPAC

AF:

0.118

AC:

455

ESP6500AA

AF:

0.113

AC:

400

ESP6500EA

AF:

0.101

AC:

731

ExAC

AF:

0.106

AC:

11817

Asia WGS

AF:

0.111

AC:

386

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30919163) -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis 5

Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Neuronal ceroid lipofuscinosis

Benign:2

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.067

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.0

PhyloP100

0.32

PrimateAI

Uncertain

0.58

ClinPred

0.099

GERP RS

2.1

PromoterAI

0.080

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

13-76991955-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over