Variant chr13-77000694-TATCTGGGAAATGAAAC-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_006493.4(CLN5):c.808_823delGGAAATGAAACATCTG(p.Gly270fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

CLN5
NM_006493.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.86

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.25 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-77000694-TATCTGGGAAATGAAAC-T is Pathogenic according to our data. Variant chr13-77000694-TATCTGGGAAATGAAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN5	NM_006493.4 linkuse as main transcript	c.808_823delGGAAATGAAACATCTG	p.Gly270fs	frameshift_variant	4/4	ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 linkuse as main transcript	c.257_272delGGAAATGAAACATCTG		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.808_823delGGAAATGAAACATCTG	p.Gly270fs	frameshift_variant	4/4	1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 linkuse as main transcript	c.565+4573_565+4588delGGAAATGAAACATCTG		intron_variant		5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000636

AC:

AN:

1461832

Hom.:

AF XY:

0.0000605

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000818

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2022	Identified with a second CLN5 variant in an individual with neuronal ceroid lipofuscinoses, however, clinical and familial segregation information was not provided (Kousi M et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 89 amino acids are replaced with 11 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21990111) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2014	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2017	- -

Neuronal ceroid lipofuscinosis

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 07, 2023	Variant summary: CLN5 c.808_823del16 (p.Gly270PhefsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Variants downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant allele was found at a frequency of 4e-06 in 251264 control chromosomes (gnomAD). c.808_823del16 has been reported in the literature in at-least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example: Kousi_2012). The following publication has been ascertained in the context of this evaluation (PMID: 21990111). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2023	This sequence change creates a premature translational stop signal (p.Gly319Phefs12) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs776933221, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 56547). This variant disrupts a region of the CLN5 protein in which other variant(s) (p.Tyr392) have been determined to be pathogenic (PMID: 9662406, 11971870, 20052765, 24038957, 24058541). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis 5

Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 10, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

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