chr8-1771527-A-G

Position:

chr8-1771527-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_018941.4(CLN8):c.473A>G(p.Tyr158Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,980 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. Y158S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CLN8
NM_018941.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.41

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 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain 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 chr8-1771527-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 802387.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.882

PP5

Variant 8-1771527-A-G is Pathogenic according to our data. Variant chr8-1771527-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1771527-A-G is described in UniProt as null. Variant chr8-1771527-A-G is described in Lovd as [Pathogenic]. Variant chr8-1771527-A-G 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.473A>G	p.Tyr158Cys	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6 linkuse as main transcript	c.473A>G	p.Tyr158Cys	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00000795

AC:

AN:

251456

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135914

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727240

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000425

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.473A>G (p.Tyr158Cys) in CLN8 gene has been previously observed in individual(s) with neuronal ceroid lipofuscinosis (Cannelli et al. 2006, Kousi et al. 2012). In at least one individual the data is consistent with the variant being in trans from a pathogenic variant. This variant has been previously reported to affect CLN8 protein function (Vantaggiato et al. 2009). The p.Tyr158Cys variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.0008%. This variant has been reported to the ClinVar database as Likely Pathogenic. The amino acid Tyr at position 158 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Tyr158Cys in CLN8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Likely pathogenic, no assertion criteria provided	literature only	Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 06, 2020	- -

Neuronal ceroid lipofuscinosis

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2023	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 158 of the CLN8 protein (p.Tyr158Cys). This variant is present in population databases (rs386834130, gnomAD 0.003%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 16570191, 21990111). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56710). 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 not expected to disrupt CLN8 protein function. Experimental studies have shown that this missense change affects CLN8 function (PMID: 19431184). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	Variant summary: CLN8 c.473A>G (p.Tyr158Cys) results in a non-conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of 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 8e-06 in 251456 control chromosomes (gnomAD). c.473A>G has been reported in the literature in multiple individuals affected with CLN8-related neuronal ceroid lipofuscinosis (examples: Cannelli_2006, DiFruscio_2015, Jilani_2019, Sharkia_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16570191, 26075876, 36011304, 31741823). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

The c.473A>G (p.Y158C) alteration is located in exon 2 (coding exon 1) of the CLN8 gene. This alteration results from a A to G substitution at nucleotide position 473, causing the tyrosine (Y) at amino acid position 158 to be replaced by a cysteine (C). Based on data from gnomAD, the G allele has an overall frequency of <0.01% (2/251456) total alleles studied. The highest observed frequency was <0.01% (1/30616) of South Asian alleles. This alteration has been detected in the homozygous state, and in conjunction with another pathogenic mutation in CLN8, in several unrelated individuals with CLN8-related neuronal ceroid lipofuscinosis (Kousi, 2012; Cannelli, 2006; Di Fruscio, 2015; Jilani, 2019). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely 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 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;D;D;.;D;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

.;.;.;.;D;.;D

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.4

M;M;M;M;.;M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-4.6

D;.;.;.;.;.;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0030

D;.;.;.;.;.;.

Sift4G

Pathogenic

0.0010

D;.;.;.;.;.;D

Polyphen

1.0

D;D;D;D;.;D;.

Vest4

0.77

MutPred

0.60

Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);

MVP

0.96

MPC

0.31

ClinPred

0.91

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.34

gMVP

0.84

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

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