8-1763878-C-CAGCCCAGGTGAGCGCTCAGGG

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018941.4(CLN8):​c.-125_-124+19dup variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 151,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 28)

Consequence

CLN8
NM_018941.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.207
Variant links:
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]
CLN8-AS1 (HGNC:55523): (CLN8 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLN8NM_018941.4 linkuse as main transcriptc.-125_-124+19dup 5_prime_UTR_variant 1/3 ENST00000331222.6 NP_061764.2
CLN8-AS1NR_134303.1 linkuse as main transcriptn.151+555_151+556insCCCTGAGCGCTCACCTGGGCT intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLN8ENST00000331222.6 linkuse as main transcriptc.-125_-124+19dup 5_prime_UTR_variant 1/31 NM_018941.4 ENSP00000328182 P1
CLN8-AS1ENST00000659375.1 linkuse as main transcriptn.75+555_75+556insCCCTGAGCGCTCACCTGGGCT intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000139
AC:
21
AN:
151238
Hom.:
0
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000722
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000591
Gnomad OTH
AF:
0.000480
GnomAD4 exome
Cov.:
0
GnomAD4 genome
AF:
0.000139
AC:
21
AN:
151346
Hom.:
0
Cov.:
28
AF XY:
0.000135
AC XY:
10
AN XY:
73958
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.000722
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000591
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.0000843
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 30, 2017A variant of uncertain significance has been identified in the CLN8 gene. The c.-125_-124+19dup21 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. 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.-125_-124+19dup21 creates a cryptic donor site downstream of the natural splice site, leading 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. -
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064793088; hg19: chr8-1712044; API