8-1771428-A-G

Position:

chr8-1771428-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

The NM_018941.4(CLN8):c.374A>G(p.Asn125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 0 hom. )

Consequence

CLN8
NM_018941.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9B:4O:1

Conservation

PhyloP100: 1.30

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:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.011771888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4 linkuse as main transcript	c.374A>G	p.Asn125Ser	missense_variant	2/3	ENST00000331222.6	NP_061764.2	Q9UBY8A0A024QZ57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6 linkuse as main transcript	c.374A>G	p.Asn125Ser	missense_variant	2/3	1	NM_018941.4	ENSP00000328182.4		Q9UBY8
KBTBD11-OT1	ENST00000635855.1 linkuse as main transcript	n.374A>G		non_coding_transcript_exon_variant	2/30	5		ENSP00000489726.1		A0A1B0GTJ5

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000974

AC:

245

AN:

251482

Hom.:

AF XY:

0.00118

AC XY:

161

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00222

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00117

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00122

AC:

1778

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

920

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00213

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00132

Gnomad4 OTH exome

AF:

0.00101

GnomAD4 genome

AF:

0.000841

AC:

128

AN:

152232

Hom.:

Cov.:

AF XY:

0.000766

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.00118

Hom.:

Bravo

AF:

0.000956

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000815

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8

Pathogenic:1Uncertain:2Benign:1Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Benign, for Ceroid lipofuscinosis, neuronal, 8, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 => Allele frequency is greater than expected for disorder. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 26, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant classified as Likely benign and reported on 07-01-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2023	See Variant Classification Assertion Criteria. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 09, 2021	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 20, 2022	Variant summary: CLN8 c.374A>G (p.Asn125Ser) results in a conservative amino acid change located in the TRAM/LAG1/CLN8 homology domain (IPR006634) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251482 control chromosomes (gnomAD), predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CLN8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.00087), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Co-occurrences with at least one other pathogenic variant has been reported in an individual homozygous for the variant of interest and homozygous for a RELN variant (c.9841del, p.Ala3281fs, Alfares_2017), providing supporting evidence for a benign role. To our knowledge, no individuals affected with Neuronal Ceroid-Lipofuscinosis and no experimental evidence demonstrating an impact on protein function has been reported. Eleven ClinVar submitters have assessed the variant since 2014: seven classified the variant as of uncertain significance, one as likely pathogenic, and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 10, 2015	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

The p.N125S variant (also known as c.374A>G), located in coding exon 1 of the CLN8 gene, results from an A to G substitution at nucleotide position 374. The asparagine at codon 125 is replaced by serine, an amino acid with highly similar properties. In one study, this alteration was listed as as a neuronal ceroid-lipofuscinoses (NCL) associated mutation; however, there was no phenotypic information provided on the individual in which it was detected (Kousi M et al. Hum. Mutat., 2012 Jan;33:42-63). This variant was also identified in the homozygous state in an individual with NCL and lissencephaly; this individual was also homozygous for a frameshift variant in the RELN gene (Alfares A et al. Mol. Genet. Metab., 2017 06;121:91-95). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -

Intellectual disability

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Jul 22, 2022

This variant has been reported in the literature in the homozygous state in at least 1 individual with a complex neurological phenotype; this individual also carried a homozygous frameshift variant in a different neurological gene (RELN). This variant was also identified in the heterozygous state in 1 individual with suspicion of a lysosomal storage disorder and this variant was also identified in 1 individual with "CLN8-related disease", though no other variants were reported in the individual (Kousi 2012 PMID: 21990111, Alfares 2017 PMID:28454995, Gheldof 2019 PMID:30548430). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.1% (19/15276) (https://gnomad.broadinstitute.org/variant/8-1771428-A-G?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Benign (Variation ID:205207). This variant amino acid Serine (Ser) is present in several species including multiple mammals and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Neuronal ceroid lipofuscinosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.44

CADD

Benign

0.61

DANN

Benign

0.42

DEOGEN2

Uncertain

0.47

.;T;T;T;T;.;T;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.74

T;.;.;.;.;T;.;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.7

.;L;L;L;L;.;L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.96

.;N;.;.;.;.;.;.

REVEL

Benign

0.28

Sift

Benign

0.28

.;T;.;.;.;.;.;.

Sift4G

Uncertain

0.016

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

Polyphen

0.034

.;B;B;B;B;.;B;.

Vest4

0.71

MVP

0.81

MPC

0.035

ClinPred

0.0090

GERP RS

-0.080

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.25

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