8-1763857-GCAGGGAGCCCGGCTGAGTGGCAGCCCAGGTGAGCGCT-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_018941.4(CLN8):c.-139_-124+21del variant causes a splice donor, splice donor 5th base, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 27)
Consequence
CLN8
NM_018941.4 splice_donor, splice_donor_5th_base, 5_prime_UTR, intron
NM_018941.4 splice_donor, splice_donor_5th_base, 5_prime_UTR, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.61
Genes affected
CLN8 (HGNC:2079): (CLN8 transmembrane ER and ERGIC protein) This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. [provided by RefSeq, Jul 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11149826 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 3, new splice context is: cagGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.-139_-124+21del | splice_donor_variant, splice_donor_5th_base_variant, 5_prime_UTR_variant, intron_variant | 1/3 | ENST00000331222.6 | NP_061764.2 | ||
CLN8-AS1 | NR_134303.1 | n.151+540_151+576del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.-139_-124+21del | splice_donor_variant, splice_donor_5th_base_variant, 5_prime_UTR_variant, intron_variant | 1/3 | 1 | NM_018941.4 | ENSP00000328182 | P1 | ||
CLN8-AS1 | ENST00000659375.1 | n.75+540_75+576del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000661 AC: 1AN: 151210Hom.: 0 Cov.: 27
GnomAD3 genomes
AF:
AC:
1
AN:
151210
Hom.:
Cov.:
27
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome AF: 0.00000661 AC: 1AN: 151210Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0AN XY: 73820
GnomAD4 genome
AF:
AC:
1
AN:
151210
Hom.:
Cov.:
27
AF XY:
AC XY:
0
AN XY:
73820
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2017 | A variant of uncertain significance has been identified in the CLN8 gene. The c. -139_-124+21del37 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. No data are available from control populations to assess the frequency of this variant. This variant spans the 3' end of the noncoding exon 1 and the donor site of intron 2. Several in-silico splice prediction models predict that c. -139_-124+21del37 variant may destroy the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Additionally, to our knowledge, splice and regulatory variants have not been reported in CLN8 in association with NCL (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at