rs188259026
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The ENST00000331222.6(CLN8):āc.509C>Gā(p.Thr170Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 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 Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T170M) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000331222.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.509C>G | p.Thr170Arg | missense_variant | 2/3 | ENST00000331222.6 | NP_061764.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.509C>G | p.Thr170Arg | missense_variant | 2/3 | 1 | NM_018941.4 | ENSP00000328182 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251224Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135830
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727214
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 23, 2022 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 170 of the CLN8 protein (p.Thr170Arg). 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. 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 expected to disrupt CLN8 protein function. This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 24767253). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at