15-68229580-T-C
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_017882.3(CLN6):c.5A>G(p.Glu2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,465,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_017882.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN6 | NM_017882.3 | c.5A>G | p.Glu2Gly | missense_variant | Exon 1 of 7 | ENST00000249806.11 | NP_060352.1 | |
CLN6 | NM_001411068.1 | c.180-10930A>G | intron_variant | Intron 1 of 6 | NP_001397997.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000533 AC: 81AN: 151858Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.000324 AC: 26AN: 80306Hom.: 1 AF XY: 0.000283 AC XY: 13AN XY: 45872
GnomAD4 exome AF: 0.000182 AC: 239AN: 1313090Hom.: 0 Cov.: 31 AF XY: 0.000184 AC XY: 119AN XY: 647624
GnomAD4 genome AF: 0.000533 AC: 81AN: 151966Hom.: 0 Cov.: 34 AF XY: 0.000633 AC XY: 47AN XY: 74308
ClinVar
Submissions by phenotype
not provided Uncertain:3
A variant of uncertain significance has been identified in the CLN6 gene. The E2G variant has beenreported previously in the homozygous state in an individual with late-infantile neuronal ceroidlipofuscinosis (Di Fruscio et al., 2015). The E2G variant is observed in 13/1008 (1.3%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). The E2G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (R5W, R6T) have been reported in the Human GeneMutation Database in association with NCL (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
- -
- -
Neuronal ceroid lipofuscinosis Benign:2
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
- -
Inborn genetic diseases Uncertain:1
The p.E2G variant (also known as c.5A>G), located in coding exon 1 of the CLN6 gene, results from an A to G substitution at nucleotide position 5. The glutamic acid at codon 2 is replaced by glycine, an amino acid with similar properties. This variant was reported as homozygous in an individual with neuronal ceroid lipofuscinosis (Di Fruscio G et al. Autophagy, 2015;11:928-38). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Ceroid lipofuscinosis, neuronal, 6A Uncertain:1
- -
Ceroid lipofuscinosis, neuronal, 6A;C5561927:Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Uncertain:1
- -
Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at