rs386834129
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_018941.4(CLN8):c.46C>A(p.Leu16Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,896 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L16R) has been classified as Uncertain significance.
Frequency
Consequence
NM_018941.4 missense
Scores
Clinical Significance
Conservation
Publications
- neuronal ceroid lipofuscinosisInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- neuronal ceroid lipofuscinosis 8Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
- neuronal ceroid lipofuscinosis 8 northern epilepsy variantInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
- autism spectrum disorderInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.46C>A | p.Leu16Met | missense_variant | Exon 2 of 3 | ENST00000331222.6 | NP_061764.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.46C>A | p.Leu16Met | missense_variant | Exon 2 of 3 | 1 | NM_018941.4 | ENSP00000328182.4 | ||
KBTBD11-OT1 | ENST00000635855.1 | n.46C>A | non_coding_transcript_exon_variant | Exon 2 of 30 | 5 | ENSP00000489726.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251488 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461890Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21AN XY: 727248 show subpopulations
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152006Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74224 show subpopulations
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis 8 Pathogenic:1Uncertain:1
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not specified Uncertain:1
Variant summary: CLN8 c.46C>A (p.Leu16Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251488 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.46C>A has been reported in the literature in the homozygous state in two siblings affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) from a consanguineous Turkish family, however it was reported as a complex allele together with c.509C>T, p.Thr170Met (Ranta_2004). To our knowledge, no other occurrences of c.46C>A in affected individuals and no experimental evidence demonstrating an impact on protein function have been reported. Therefore, this report does not provide unequivocal conclusions about association of the variant with disease. The following publication has been ascertained in the context of this evaluation (PMID: 15024724). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
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Neuronal ceroid lipofuscinosis Uncertain:1
This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 16 of the CLN8 protein (p.Leu16Met). This variant is present in population databases (rs386834129, gnomAD 0.01%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 15024724). ClinVar contains an entry for this variant (Variation ID: 56709). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Neuronal ceroid lipofuscinosis 8;C1864923:Neuronal ceroid lipofuscinosis 8 northern epilepsy variant Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at