16-28491759-T-G
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_001042432.2(CLN3):āc.1A>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,554 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 Pathogenic (ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000014 ( 0 hom. )
Consequence
CLN3
NM_001042432.2 start_lost
NM_001042432.2 start_lost
Scores
5
3
3
Clinical Significance
Conservation
PhyloP100: 2.17
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.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_001042432.2 (CLN3) was described as [Likely_pathogenic] in ClinVar as 371317
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-28491759-T-G is Pathogenic according to our data. Variant chr16-28491759-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 56257.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28491759-T-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.1A>C | p.Met1? | start_lost | 2/16 | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.1A>C | p.Met1? | start_lost | 2/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461554Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727082
GnomAD4 exome
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2
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1461554
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31
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1
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727082
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 20, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 56257). Disruption of the initiator codon has been observed in individuals with neuronal ceroid lipofuscinosis and may be associated with a milder phenotype (PMID: 21990111, 32154056). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. - |
Neuronal ceroid lipofuscinosis 3 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Benign
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;.;D;.;D;D;.;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;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
0.73, 0.83, 0.91, 0.43
.;P;P;.;.;.;.;P;P;P;.;B;.;.;.;.
Vest4
0.73, 0.82, 0.68, 0.84, 0.80, 0.55
MutPred
Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);
MVP
0.91
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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