rs199727787

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006493.4(CLN5):c.76T>C(p.Trp26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,605,492 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W26S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 12 hom. )

Consequence

CLN5
NM_006493.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: -0.0160

Publications

5 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004347682).

BP6

Variant 13-76992174-T-C is Benign according to our data. Variant chr13-76992174-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205127.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00122 (185/152262) while in subpopulation SAS AF = 0.00228 (11/4818). AF 95% confidence interval is 0.00128. There are 2 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4 link	c.76T>C	p.Trp26Arg	missense_variant	Exon 1 of 4	ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 link	c.76T>C	p.Trp26Arg	missense_variant	Exon 1 of 5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9 link	c.76T>C	p.Trp26Arg	missense_variant	Exon 1 of 4	1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 link	c.76T>C	p.Trp26Arg	missense_variant	Exon 1 of 5	5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

185

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0159

Gnomad NFE

AF:

0.000897

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00183

AC:

410

AN:

223686

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.000151

Gnomad AMR exome

AF:

0.000357

Gnomad ASJ exome

AF:

0.0199

Gnomad EAS exome

AF:

0.0000579

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00124

Gnomad OTH exome

AF:

0.00361

GnomAD4 exome

AF:

0.00116

AC:

1681

AN:

1453230

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

898

AN XY:

722762

show subpopulations

African (AFR)

AF:

0.000572

AC:

AN:

33198

American (AMR)

AF:

0.000271

AC:

AN:

44284

Ashkenazi Jewish (ASJ)

AF:

0.0223

AC:

578

AN:

25930

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39548

South Asian (SAS)

AF:

0.00227

AC:

195

AN:

85784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50202

Middle Eastern (MID)

AF:

0.0164

AC:

AN:

4564

European-Non Finnish (NFE)

AF:

0.000536

AC:

595

AN:

1109810

Other (OTH)

AF:

0.00344

AC:

206

AN:

59910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

116

232

348

464

580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00122

AC:

185

AN:

152262

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41554

American (AMR)

AF:

0.000458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00228

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0171

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00236

Hom.:

Bravo

AF:

0.00134

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00204

AC:

ExAC

AF:

0.00145

AC:

173

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLN5: BS1, BS2 -

Neuronal ceroid lipofuscinosis 5

Uncertain:1Benign:3

Oct 15, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Likely Benign, for Ceroid lipofuscinosis, neuronal, 5, autosomal recessive. The following ACMG Tag(s) were applied: 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. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:2

Jun 16, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Nov 16, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis

Benign:2

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Aug 09, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

CLN5-related disorder

Benign:1

Jul 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.26

CADD

Benign

9.3

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.074

T;T;T;T;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.27

T;.;T;.;.;.

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0043

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

.;.;N;.;.;.

PhyloP100

-0.016

PrimateAI

Uncertain

0.71

REVEL

Benign

0.25

Polyphen

0.0

.;.;B;.;.;.

MutPred

0.61

.;.;Gain of disorder (P = 0.0113);.;.;.;

MVP

0.33

MPC

0.32

ClinPred

0.0035

GERP RS

-1.9

PromoterAI

-0.41

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.084

Mutation Taster

=95/5

polymorphism

(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

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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