rs386833702

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1_StrongPM2PP3_StrongPP5_Very_Strong

The NM_001042432.2(CLN3):c.1198-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000118 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 6.69

Variant links:

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.27031133 fraction of the gene.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-28477636-C-A is Pathogenic according to our data. Variant chr16-28477636-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28477636-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2 linkuse as main transcript	c.1198-1G>T		splice_acceptor_variant		ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2 linkuse as main transcript	c.1198-1G>T		splice_acceptor_variant		1	NM_001042432.2	P1	Q13286-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250410

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135418

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	This sequence change affects an acceptor splice site in intron 15 of the CLN3 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs386833702, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with juvenile neuronal ceroid lipofuscinosis (PMID: 9311735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS14-1G>T. ClinVar contains an entry for this variant (Variation ID: 56251). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2023	Variant summary: CLN3 c.1198-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. Three predict the variant creates or strengthens a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Munroe_1997), resulting in the use of a cryptic splice acceptor site and a premature stop codon. The variant allele was found at a frequency of 8e-06 in 250410 control chromosomes (gnomAD). c.1198-1G>T has been reported in the literature in related individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) who were compound heterozygous with a pathogenic large deletion change (Munroe_1997). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 9311735). Three 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. -

Neuronal ceroid lipofuscinosis 3

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	Counsyl	Aug 24, 2017	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2018

The c.1198-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 15 of the CLN3 gene. Alterations that disrupt the canonical splice site are typically deleterious in nature; however, this alteration occurs at the splice acceptor site of the last intron of CLN3 and is not expected to trigger nonsense-mediated mRNA decay. This variant was detected in three affected siblings with juvenile-onset neuronal ceroid lipofuscinosis, who had a common deletions of exons 7 and 8 (c.461-280_677+382del) on the other chromosome (Munroe PB et al. Am. J. Hum. Genet., 1997 Aug;61:310-6). RT-PCR analysis in one of the siblings revealed that this alteration activated a cryptic splice acceptor site in exon 15, resulting in introduction of a premature stop codon. In addition, a likely pathogenic variant (p.D416G) in the last exon has been reported in multiple affected individuals (Kwon JM et al. Neurology, 2011 Nov;77:1801-7; Lojewski X et al. Hum. Mol. Genet., 2014 Apr;23:2005-22), suggesting functional importance of amino acids affected by the premature stop codon. Based on data from gnomAD, the T allele has an overall frequency of approximately 0.0008% (2/250410). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is also predicted to abolish the native splice acceptor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.38

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

GERP RS

4.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.54

Position offset: -6

DS_AL_spliceai

0.99

Position offset: -1

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

Other links and lift over