16-28484003-T-G
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_001042432.2(CLN3):c.790+3A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,602,734 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00011 ( 3 hom. )
Consequence
CLN3
NM_001042432.2 splice_donor_region, intron
NM_001042432.2 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9695
1
1
Clinical Significance
Conservation
PhyloP100: -0.0590
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 Likely_benign. Variant got -3 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN3 | NM_001042432.2 | c.790+3A>C | splice_donor_region_variant, intron_variant | ENST00000636147.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN3 | ENST00000636147.2 | c.790+3A>C | splice_donor_region_variant, intron_variant | 1 | NM_001042432.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152194Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000181 AC: 42AN: 232186Hom.: 2 AF XY: 0.000271 AC XY: 34AN XY: 125344
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GnomAD4 exome AF: 0.000110 AC: 159AN: 1450422Hom.: 3 Cov.: 30 AF XY: 0.000176 AC XY: 127AN XY: 720540
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GnomAD4 genome AF: 0.0000328 AC: 5AN: 152312Hom.: 0 Cov.: 31 AF XY: 0.0000671 AC XY: 5AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 3 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Likely pathogenic, flagged submission | literature only | Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM) | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 11, 2021 | Variant summary: CLN3 c.790+3A>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant slightly weakens the canonical 5' splice donor site. One predicts the variant abolishes the canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 232186 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CLN3 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00018 vs 0.0016), allowing no conclusion about variant significance. c.790+3A>C has been reported in the literature as a compound heterozygous genotype in at-least one individual with CLN3 disease (example, Mirza_2019) and as a non-informative (second allele not specified) genotype in a study reporting an update on the spectrum of CLN3 gene mutations (example, Kousi_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign, n=1; VUS, n=2; Likely pathogenic, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Ceroid lipofuscinosis, neuronal, 3, protracted Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 30, 2023 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2017 | c.790+3 A>C: IVS10+3 A>C in intron 10 of the CLN3 gene (NM_001042432.1). The c.790+3 A>C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Several in-silico splice prediction models predict that c.790+3 A>C damages the natural donor site and leads to abnormal gene splicing. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY,INFANT-EPI panel(s). - |
Neuronal ceroid lipofuscinosis Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -22
Find out detailed SpliceAI scores and Pangolin per-transcript scores at