8-1771056-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_018941.4(CLN8):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CLN8
NM_018941.4 start_lost

Scores

8
4
4

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.79
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_018941.4 (CLN8) was described as [Likely_pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-1771056-T-C is Pathogenic according to our data. Variant chr8-1771056-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555468.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLN8NM_018941.4 linkuse as main transcriptc.2T>C p.Met1? start_lost 2/3 ENST00000331222.6 NP_061764.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLN8ENST00000331222.6 linkuse as main transcriptc.2T>C p.Met1? start_lost 2/31 NM_018941.4 ENSP00000328182 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingCounsylDec 08, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.43
CADD
Benign
19
DANN
Benign
0.86
DEOGEN2
Benign
0.17
.;T;T;T;T;.;T;.;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.90
D;.;.;.;.;D;.;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationTaster
Benign
1.0
D
PROVEAN
Benign
-0.79
.;N;.;.;.;.;.;.;.
REVEL
Uncertain
0.64
Sift
Pathogenic
0.0
.;D;.;.;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;.;.;.;.;.;D;.
Polyphen
1.0
.;D;D;D;D;.;D;.;.
Vest4
0.96
MutPred
0.99
Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);Gain of glycosylation at M1 (P = 0.0021);
MVP
0.97
ClinPred
0.92
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.83
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1554448874; hg19: chr8-1719222; API