16-28482107-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042432.2(CLN3):​c.1054C>T​(p.Gln352*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,832 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 stop_gained, splice_region

Scores

5
1
1
Splicing: ADA: 0.9995
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 16-28482107-G-A is Pathogenic according to our data. Variant chr16-28482107-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 56246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28482107-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLN3NM_001042432.2 linkc.1054C>T p.Gln352* stop_gained, splice_region_variant Exon 14 of 16 ENST00000636147.2 NP_001035897.1 Q13286-1A0A024QZB8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLN3ENST00000636147.2 linkc.1054C>T p.Gln352* stop_gained, splice_region_variant Exon 14 of 16 1 NM_001042432.2 ENSP00000490105.1 Q13286-1
ENSG00000261832ENST00000637378.1 linkc.226C>T p.Gln76* stop_gained, splice_region_variant Exon 4 of 10 5 ENSP00000490831.1 A0A1B0GW90

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
31
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000814
AC:
2
AN:
245602
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
132850
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:
0.0000180
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000548
AC:
8
AN:
1459710
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726002
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:
0.00000720
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
31
AF XY:
0.0000404
AC XY:
3
AN XY:
74318
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:4
Jan 25, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Aug 10, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 06, 2018
Counsyl
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:3
-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 10, 2017
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Q352X nonsense variant in the CLN3 gene has been reported previously in association with juvenile neuronal ceroid lipofucinosis (Munroe et al., 1997, Miller et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q352X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). Therefore, this nonsense variant is considered to be a pathogenic variant. -

Neuronal ceroid lipofuscinosis Pathogenic:2
May 01, 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.Gln352*) in the CLN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN3 are known to be pathogenic (PMID: 9311735, 28542676). This variant is present in population databases (rs386833697, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with CLN3-related conditions (PMID: 9311735, 23539563). ClinVar contains an entry for this variant (Variation ID: 56246). 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. -

Dec 17, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CLN3 c.1054C>T (p.Gln352X) 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. The variant allele was found at a frequency of 8.1e-06 in 245602 control chromosomes (gnomAD). c.1054C>T has been reported in the literature in multiple individuals affected with Juvenile Neuronal Ceroid-Lipofuscinosis (Juvenile Batten Disease) (examples: Munroe_1997, Miller_2013, Kousi_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence, and demonstrated that the CLN3 mRNA level was decreased in LCLs derived from a homozygous patient, presumably due to nonsense mediated decay (Miller_2013). Three ClinVar submitter have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy Pathogenic:1
Jan 01, 2023
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
56
DANN
Uncertain
1.0
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.93
FATHMM_MKL
Pathogenic
0.99
D
Vest4
0.98, 0.96, 0.95, 0.97, 0.95
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.67
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.67
Position offset: 2
DS_DL_spliceai
0.44
Position offset: -2

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.

Other links and lift over

dbSNP: rs386833697; hg19: chr16-28493428; API