rs104894060

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_018941.4(CLN8):c.610C>T(p.Arg204Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,614,116 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R204H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CLN8
NM_018941.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.56

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a domain TLC (size 200) in uniprot entity CLN8_HUMAN there are 39 pathogenic changes around while only 14 benign (74%) in NM_018941.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-1780316-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1919167.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 8-1780316-C-T is Pathogenic according to our data. Variant chr8-1780316-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1780316-C-T is described in UniProt as null. Variant chr8-1780316-C-T is described in Lovd as [Pathogenic]. Variant chr8-1780316-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4 linkuse as main transcript	c.610C>T	p.Arg204Cys	missense_variant	3/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6 linkuse as main transcript	c.610C>T	p.Arg204Cys	missense_variant	3/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251318

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2020	Variant summary: CLN8 c.610C>T (p.Arg204Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 252044 control chromosomes (gnomAD and publication). c.610C>T has been reported in the literature in multiple individuals affected with late infantile neuronal ceroid lipofuscinoses (Ranta_2004, Lee_2014) and cosegregated with the disease phenotype in the families (Ranta_2004). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2004	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Aug 14, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 12, 2018	- -

CLN8-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Sep 13, 2022

PM2, PM3_Strong, PP1, PP3 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 13, 2022

Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25326637, 15024724, 30293248, 15160397, 19807737, 14997939, 15074367, 21990111, 26026925, 31589614) -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 204 of the CLN8 protein (p.Arg204Cys). This variant is present in population databases (rs104894060, gnomAD 0.006%). This missense change has been observed in individuals with neuronal ceroid lipofuscinosis (PMID: 15024724, 25326637). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2804). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLN8 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect CLN8 function (PMID: 15160397). This variant disrupts the p.Arg204 amino acid residue in CLN8. Other variant(s) that disrupt this residue have been observed in individuals with CLN8-related conditions (PMID: 15024724, 19807737, 23374165), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis 8;C1864923:Neuronal ceroid lipofuscinosis 8 northern epilepsy variant

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.53

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;D;D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.6

M;M;M;M;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-4.0

D;.;.;.;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.;.;.;.

Sift4G

Pathogenic

0.0

D;.;.;.;.

Polyphen

1.0

D;D;D;D;D

Vest4

0.74

MutPred

0.81

Loss of MoRF binding (P = 0.0582);Loss of MoRF binding (P = 0.0582);Loss of MoRF binding (P = 0.0582);Loss of MoRF binding (P = 0.0582);Loss of MoRF binding (P = 0.0582);

MVP

0.98

MPC

0.32

ClinPred

0.83

GERP RS

4.3

Varity_R

0.54

gMVP

0.97

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over