8-1771428-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N125I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:4 O:1
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.011771888).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.374A>G	p.Asn125Ser	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.374A>G	p.Asn125Ser	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152112 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00118 AC XY: 161 AN XY: 135920

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.: 0 Cov.: 32 AF XY: 0.00127 AC XY: 920 AN XY: 727248

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.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74414

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.: 0

Bravo AF: 0.000956

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000815 AC: 99

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8 Pathogenic:1 Uncertain:2 Benign:1 Other:1

Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
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. -
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]. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 26, 2020	- -
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. -

not provided Uncertain:3 Benign: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:1 Benign: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

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	0.61
Dann	Benign	0.42
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.74	T;.;.;.;.;T;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.012	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	0.86	N
PrimateAI	Benign	0.31	T
Polyphen		0.034	.;B;B;B;B;.;B;.
Vest4		0.71
MVP		0.81
MPC		0.035
ClinPred		0.0090	T
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

Other links and lift over

dbSNP: rs142269885; hg19: chr8-1719594;