chr8-1771055-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_018941.4(CLN8):āc.1A>Gā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000991 in 1,614,086 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 Pathogenic (ā ā ).
Frequency
Genomes: š 0.000020 ( 0 hom., cov: 32)
Exomes š: 0.0000089 ( 0 hom. )
Consequence
CLN8
NM_018941.4 start_lost
NM_018941.4 start_lost
Scores
9
3
4
Clinical Significance
Conservation
PhyloP100: 6.01
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_018941.4 (CLN8) was described as [Pathogenic] in ClinVar as 2749928
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-1771055-A-G is Pathogenic according to our data. Variant chr8-1771055-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 487522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.1A>G | p.Met1? | start_lost | 2/3 | ENST00000331222.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLN8 | ENST00000331222.6 | c.1A>G | p.Met1? | start_lost | 2/3 | 1 | NM_018941.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251470Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
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GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727234
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74418
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Neuronal ceroid lipofuscinosis 8 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Translational Research Program on Neuronal Ceroid Lipofuscinosis, Center for the Study of Inborn Errors of Metabolism | - | This mutation was detected in heterozygous state, combined with a c.792C>G mutation. - |
Neuronal ceroid lipofuscinosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 04, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CLN8 protein in which other variant(s) (p.Arg24Gly) have been determined to be pathogenic (PMID: 10508524, 10861296, 15160397, 16828266). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 487522). Disruption of the initiator codon has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis type 8 (PMID: 30741402, 31069529). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CLN8 mRNA. The next in-frame methionine is located at codon 28. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;T;T;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;.;.;.;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D
PROVEAN
Benign
.;N;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;D;.;.;.;.;.;D;.
Polyphen
1.0
.;D;D;D;D;.;D;.;.
Vest4
0.95
MVP
0.96
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at