rs386833703

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001042432.2(CLN3):ā€‹c.1247A>Gā€‹(p.Asp416Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,678 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 Likely pathogenic (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

10
7
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.07
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 14 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 16-28477586-T-C is Pathogenic according to our data. Variant chr16-28477586-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28477586-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLN3NM_001042432.2 linkuse as main transcriptc.1247A>G p.Asp416Gly missense_variant 16/16 ENST00000636147.2 NP_001035897.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLN3ENST00000636147.2 linkuse as main transcriptc.1247A>G p.Asp416Gly missense_variant 16/161 NM_001042432.2 ENSP00000490105 P1Q13286-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151910
Hom.:
0
Cov.:
32
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:
0.00000399
AC:
1
AN:
250758
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135584
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:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461768
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727168
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151910
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74208
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:
0.00000378
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:2
Likely pathogenic, no assertion criteria providedliterature onlyJuha Muilu Group; Institute for Molecular Medicine Finland (FIMM)-- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 27, 2024- -
Neuronal ceroid lipofuscinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 27, 2023Variant summary: CLN3 c.1247A>G (p.Asp416Gly) results in a non-conservative amino acid change to a highly conserved residue (HGMD) in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250758 control chromosomes (gnomAD). c.1247A>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Kwon_2011, Lojewski_2014, Sleat_2017), and they were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. Publications report experimental evidence evaluating an impact of the variant protein in iPSCs, finding reductions in TRPML1 activation, endolysosomal localization, and proteolysis, as well as expansion of the lysosomal compartment (Prat Castro_2022, Scotto Rosato_2022). The following publications have been ascertained in the context of this evaluation (PMID: 22013180, 24271013, 28792770, 36139381, 35929194). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.56
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;.;.;D;.;.;D;D;D;.;D;.;.
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.95
.;.;D;.;.;D;D;D;.;D;D;D;.;D
M_CAP
Pathogenic
0.74
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H;.;.;.;.;.;.;H;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-5.5
.;D;.;.;D;D;D;.;D;.;D;.;.;D
REVEL
Pathogenic
0.91
Sift
Benign
0.049
.;D;.;.;D;D;D;.;D;.;D;.;.;D
Sift4G
Uncertain
0.033
.;.;D;.;D;D;D;.;D;.;D;.;.;.
Polyphen
1.0
D;D;.;.;D;.;.;.;D;D;D;D;.;D
Vest4
0.73, 0.84, 0.82, 0.84, 0.83, 0.88
MutPred
0.97
Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;.;.;.;.;.;Loss of helix (P = 0.0237);.;.;.;.;.;
MVP
0.97
MPC
0.73
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.86
gMVP
0.93

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs386833703; hg19: chr16-28488907; API