rs104894385

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006493.4(CLN5):c.78G>A(p.Trp26*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,453,728 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CLN5
NM_006493.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 1.35

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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 134 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-76992176-G-A is Pathogenic according to our data. Variant chr13-76992176-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4 link	c.78G>A	p.Trp26*	stop_gained	Exon 1 of 4	ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 link	c.78G>A	p.Trp26*	stop_gained	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.78G>A	p.Trp26*	stop_gained	Exon 1 of 4	1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 link	c.78G>A	p.Trp26*	stop_gained	Exon 1 of 5	5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000268

AC:

AN:

224264

AF XY:

0.0000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000513

Gnomad OTH exome

AF:

0.000180

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1453728

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

723092

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33256

American (AMR)

AF:

0.00

AC:

AN:

44326

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39580

South Asian (SAS)

AF:

0.00

AC:

AN:

85800

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4596

European-Non Finnish (NFE)

AF:

0.00000991

AC:

AN:

1110118

Other (OTH)

AF:

0.000100

AC:

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000504

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5

Pathogenic:3Other:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 17, 2017

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Neuronal ceroid lipofuscinosis

Pathogenic:2

Dec 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp75*) in the CLN5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN5 are known to be pathogenic (PMID: 20157158). This variant is present in population databases (rs104894385, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis, and a CLN5-related condition (PMID: 9662406; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2565). For these reasons, this variant has been classified as Pathogenic. -

Jan 09, 2021

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Benign

0.15

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.18

PhyloP100

1.4

GERP RS

3.1

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=9/191

disease causing (ClinVar)

(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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over