rs386833708
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_001042432.2(CLN3):āc.1A>Gā(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 0.00000274 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 Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
CLN3
NM_001042432.2 start_lost
NM_001042432.2 start_lost
Scores
5
4
2
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 20 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-C is Pathogenic according to our data. Variant chr16-28491759-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.1A>G | 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>G | p.Met1? | start_lost | 2/16 | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250966Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135700
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461554Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727082
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GnomAD4 genome ? Cov.: 32
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?
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32
ExAC
?
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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 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. This variant is present in population databases (rs386833708, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with Neuronal ceroid lipofuscinosis and/or retinitis pigmentosa (PMID: 32154056; Invitae). ClinVar contains an entry for this variant (Variation ID: 550268). For these reasons, this variant has been classified as Pathogenic. - |
CLN3-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 28, 2023 | The CLN3 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant has not been reported in the literature, however other variant c.1A>C disrupting initiation codon has been reported in compound heterozygous state in three individuals with attenuated form of CLN3 disease (Kuper et al 2020. PubMed ID: 32154056). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-28503080-T-C). In summary, we interpret this variant as likely pathogenic. - |
Neuronal ceroid lipofuscinosis 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 27, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
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
0.86, 0.92, 0.98, 0.63
.;P;P;.;.;.;.;P;P;D;.;P;.;.;.;.
Vest4
0.70, 0.81, 0.81, 0.76, 0.82, 0.78, 0.61
MutPred
Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);
MVP
0.93
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