rs373957283
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_018941.4(CLN8):c.200C>A(p.Ala67Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CLN8
NM_018941.4 missense
NM_018941.4 missense
Scores
8
8
3
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: 5.60
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a domain TLC (size 200) in uniprot entity CLN8_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_018941.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.845
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN8 | NM_018941.4 | c.200C>A | p.Ala67Glu | 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.200C>A | p.Ala67Glu | missense_variant | 2/3 | 1 | NM_018941.4 | ENSP00000328182.4 | ||
KBTBD11-OT1 | ENST00000635855.1 | n.200C>A | non_coding_transcript_exon_variant | 2/30 | 5 | ENSP00000489726.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461202Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726760
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74290
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ClinVar
Not reported inComputational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
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
Uncertain
D
MutationAssessor
Uncertain
.;M;M;M;M;.;M;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;.;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.;.;.;.;.;.
Sift4G
Pathogenic
D;D;.;.;.;.;.;D;.
Polyphen
1.0
.;D;D;D;D;.;D;.;.
Vest4
0.78
MutPred
Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);Loss of MoRF binding (P = 0.0748);
MVP
0.94
MPC
0.30
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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