rs571617007

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_018941.4(CLN8):c.386G>A(p.Arg129Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

CLN8
NM_018941.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.94

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 2 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=0.0851126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4 linkuse as main transcript	c.386G>A	p.Arg129Gln	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.386G>A	p.Arg129Gln	missense_variant	2/3	1	NM_018941.4	ENSP00000328182.4		Q9UBY8
KBTBD11-OT1	ENST00000635855.1 linkuse as main transcript	n.386G>A		non_coding_transcript_exon_variant	2/30	5		ENSP00000489726.1		A0A1B0GTJ5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251482

Hom.:

AF XY:

0.000147

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000581

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2017

The R129Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in11/25792 (0.04%) alleles from individuals of European background, in large population cohorts (Lek et al., 2016). The R129Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure asthese residues differ in some properties. However, this substitution occurs at a position that is not conserved, and insilico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Neuronal ceroid lipofuscinosis 8

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 10, 2020

- -

Neuronal ceroid lipofuscinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 129 of the CLN8 protein (p.Arg129Gln). This variant is present in population databases (rs571617007, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CLN8-related conditions. ClinVar contains an entry for this variant (Variation ID: 421797). 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 with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

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

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.82

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

M_CAP

Benign

0.079

MetaRNN

Benign

0.085

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

MetaSVM

Benign

-0.31

MutationAssessor

Uncertain

2.1

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

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

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

REVEL

Uncertain

0.30

Sift

Benign

0.091

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

Sift4G

Benign

0.17

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

Polyphen

0.99

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

Vest4

0.26

MutPred

0.54

Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);Loss of stability (P = 0.0863);

MVP

0.90

MPC

0.043

ClinPred

0.049

GERP RS

-0.16

Varity_R

0.072

gMVP

0.36

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