rs143578698

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 13/22 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. S308R) has been classified as Uncertain significance.

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

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

ceroid lipofuscinosis, neuronal, 6A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
ceroid lipofuscinosis, neuronal, 6B (Kufs type)
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

CLN6 links:

ENSG00000260007 (HGNC:):

ENSG00000260007 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 198573.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3 link	c.923G>C	p.Ser308Thr	missense_variant	Exon 7 of 7	ENST00000249806.11	NP_060352.1	Q9NWW5-1A0A024R601
CLN6	NM_001411068.1 link	c.1019G>C	p.Ser340Thr	missense_variant	Exon 7 of 7		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 link	c.923G>C	p.Ser308Thr	missense_variant	Exon 7 of 7	1	NM_017882.3	ENSP00000249806.5		Q9NWW5-1
ENSG00000260007	ENST00000562767.2 link	c.84-10525G>C		intron_variant	Intron 1 of 2	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

GnomAD2 exomes

AF:

0.00186

AC:

466

AN:

250784

AF XY:

0.00185

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 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

African (AFR)

AF:

0.000316

AC:

AN:

31654

American (AMR)

AF:

0.000116

AC:

AN:

43104

Ashkenazi Jewish (ASJ)

AF:

0.000209

AC:

AN:

23976

East Asian (EAS)

AF:

0.00

AC:

AN:

34208

South Asian (SAS)

AF:

0.00

AC:

AN:

85804

European-Finnish (FIN)

AF:

0.00267

AC:

130

AN:

48734

Middle Eastern (MID)

AF:

0.000186

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.00292

AC:

3143

AN:

1078040

Other (OTH)

AF:

0.00162

AC:

AN:

56770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00162

AC:

243

AN:

149982

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

104

AN XY:

73230

show subpopulations

African (AFR)

AF:

0.000463

AC:

AN:

41058

American (AMR)

AF:

0.000529

AC:

AN:

15112

Ashkenazi Jewish (ASJ)

AF:

0.000291

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

4936

South Asian (SAS)

AF:

0.00

AC:

AN:

4596

European-Finnish (FIN)

AF:

0.00157

AC:

AN:

10164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00280

AC:

189

AN:

67388

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jul 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25359263, 30548430, 21549341) -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLN6: BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 14, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 23, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis

Uncertain:1Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 16, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CLN6-related disorder

Uncertain:1

May 31, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 11, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.;.

PhyloP100

0.75

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

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over