rs386833970

Positions:

• chr13-76992238-T-TC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006493.4(CLN5):​c.144dup​(p.Ser49LeufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CLN5 NM_006493.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.220

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-76992238-T-TC is Pathogenic according to our data. Variant chr13-76992238-T-TC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56532.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	c.144dup	p.Ser49LeufsTer13	frameshift_variant	1/4	ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.144dup	p.Ser49LeufsTer13	frameshift_variant	1/5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.144dup	p.Ser49LeufsTer13	frameshift_variant	1/4	1	NM_006493.4	ENSP00000366673	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436028 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 713664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000234

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 5 Pathogenic:2

Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 14, 2022	- -

Neuronal ceroid lipofuscinosis Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2021	Variant summary: CLN5 c.291dupC (p.Ser98LeufsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 203636 control chromosomes. c.291dupC has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Kousi_2012, Kohan_2015) and has also been subsequently cited by others. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 03, 2023	This sequence change creates a premature translational stop signal (p.Ser98Leufs*13) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis type 5 (CLN5) (PMID: 21990111). ClinVar contains an entry for this variant (Variation ID: 56532). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs386833970; hg19: chr13-77566373;