rs386833703
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001042432.2(CLN3):āc.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
NM_001042432.2 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 5.07
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]
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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 |
---|---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.1247A>G | p.Asp416Gly | missense_variant | 16/16 | 1 | NM_001042432.2 | ENSP00000490105 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250758Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135584
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461768Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727168
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151910Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74208
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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 provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 27, 2023 | Variant 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;D;.;.;D;D;D;.;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;.;D;.;.;D;D;D;.;D;D;D;.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.;.;.;.;.;H;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;.;D;D;D;.;D;.;D;.;.;D
REVEL
Pathogenic
Sift
Benign
.;D;.;.;D;D;D;.;D;.;D;.;.;D
Sift4G
Uncertain
.;.;D;.;D;D;D;.;D;.;D;.;.;.
Polyphen
D;D;.;.;D;.;.;.;D;D;D;D;.;D
Vest4
0.73, 0.84, 0.82, 0.84, 0.83, 0.88
MutPred
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
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at