rs143578698

Positions:

chr15-68208153-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017882.3(CLN6):c.923G>C(p.Ser308Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,557,662 control chromosomes in the GnomAD database, including 10 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 0.754

Variant links:

Genes affected

CLN6 (HGNC:2077): (CLN6 transmembrane ER protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function. [provided by RefSeq, Oct 2008]

CLN6 links:

ENSG00000260007 (HGNC:):

ENSG00000260007 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010468572).

BP6

Variant 15-68208153-C-G is Benign according to our data. Variant chr15-68208153-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198573.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=8, Benign=1}. Variant chr15-68208153-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00162 (243/149982) while in subpopulation NFE AF= 0.0028 (189/67388). AF 95% confidence interval is 0.00248. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3 linkuse as main transcript	c.923G>C	p.Ser308Thr	missense_variant	7/7	ENST00000249806.11	NP_060352.1	Q9NWW5-1A0A024R601
CLN6	NM_001411068.1 linkuse as main transcript	c.1019G>C	p.Ser340Thr	missense_variant	7/7		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 linkuse as main transcript	c.923G>C	p.Ser308Thr	missense_variant	7/7	1	NM_017882.3	ENSP00000249806.5		Q9NWW5-1
ENSG00000260007	ENST00000562767.2 linkuse as main transcript	c.84-10525G>C		intron_variant		3		ENSP00000456336.1		H3BRN7

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

243

AN:

149868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000464

Gnomad AMI

AF:

0.00774

Gnomad AMR

AF:

0.000530

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00280

Gnomad OTH

AF:

0.00145

GnomAD3 exomes

AF:

0.00186

AC:

466

AN:

250784

Hom.:

AF XY:

0.00185

AC XY:

251

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.00349

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00241

AC:

3386

AN:

1407680

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1598

AN XY:

700652

show subpopulations

Gnomad4 AFR exome

AF:

0.000316

Gnomad4 AMR exome

AF:

0.000116

Gnomad4 ASJ exome

AF:

0.000209

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00267

Gnomad4 NFE exome

AF:

0.00292

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.00162

AC:

243

AN:

149982

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

104

AN XY:

73230

show subpopulations

Gnomad4 AFR

AF:

0.000463

Gnomad4 AMR

AF:

0.000529

Gnomad4 ASJ

AF:

0.000291

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00157

Gnomad4 NFE

AF:

0.00280

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.00219

Hom.:

Bravo

AF:

0.00151

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00237

AC:

288

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	This variant is associated with the following publications: (PMID: 25359263, 30548430, 21549341) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CLN6: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 23, 2020	- -

Neuronal ceroid lipofuscinosis

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2016

- -

CLN6-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2023

The CLN6 c.923G>C variant is predicted to result in the amino acid substitution p.Ser308Thr. This variant has been previously reported along with two other variants in the CLN6 gene in an individual with major adult form of neuronal ceroid lipofuscinosis (Family Ku8, Arsov et al. 2011. PubMed ID: 21549341). This variant was also observed in the heterozygous state in a cohort of individuals with suspected lysosomal storage disease and reported as a variant of uncertain significance (Table 3, Gheldof et al. 2019. PubMed ID: 30548430). This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-68500491-C-G), which is more common than expected for a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2018

The p.S308T variant (also known as c.923G>C), located in coding exon 7 of the CLN6 gene, results from a G to C substitution at nucleotide position 923. The serine at codon 308 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was detected in conjunction with two additional CLN6 alterations c.150C>G (p.T50*) and c.231C>G (p.N77K) in an individual with Kufs disease; however, the phase of these three alterations was not confirmed (Arsov T et al. Am. J. Hum. Genet., 2011 May;88:566-73). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ceroid lipofuscinosis, neuronal, 6A;C5561927:Ceroid lipofuscinosis, neuronal, 6B (Kufs type)

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

CLN6 NM_017882.2 exon 7 p.Ser308Thr (c.923G>C): This variant has not been reported in the literature and is present in 0.3% (435/128540) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-68500491-C-G). This variant is present in ClinVar (Variation ID:198573). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Adult neuronal ceroid lipofuscinosis;C5551375:Ceroid lipofuscinosis, neuronal, 6A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;T;T;.;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.68

T;T;T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.010

T;T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.6

L;.;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.91

N;N;N;N;.

REVEL

Uncertain

0.34

Sift

Benign

0.11

T;T;T;D;.

Sift4G

Benign

0.26

T;T;T;T;.

Polyphen

0.37

B;.;.;.;.

Vest4

0.20

MVP

0.93

MPC

0.31

ClinPred

0.017

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.41

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