Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7
The NM_001042432.2(CLN3):c.768C>T(p.Thr256=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,610,850 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T256T) has been classified as Likely benign.
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]
Verdict is Likely_benign. Variant got -6 ACMG points.
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-28484028-G-A is Benign according to our data. Variant chr16-28484028-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93505.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=2, Likely_benign=3}. Variant chr16-28484028-G-A is described in Lovd as [Benign]. Variant chr16-28484028-G-A is described in Lovd as [Likely_benign].
BP7
?
BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-3.23 with no splicing effect.
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Dec 14, 2015
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Likely benign, criteria provided, single submitter
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 12, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Benign:2
Benign, criteria provided, single submitter
clinical testing
Athena Diagnostics
Mar 09, 2018
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Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jun 14, 2016
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Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 08, 2017
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -