rs149692285

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000638076.1(CLN6):n.494C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,206 control chromosomes in the GnomAD database, including 204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 32)

Exomes 𝑓: 0.015 ( 179 hom. )

Consequence

CLN6
ENST00000638076.1 non_coding_transcript_exon

Scores

Splicing: ADA: 0.001581

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12

Conservation

PhyloP100: -0.0910

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026243627).

BP6

Variant 15-68211667-G-A is Benign according to our data. Variant chr15-68211667-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.013 (1977/152212) while in subpopulation AMR AF = 0.0212 (325/15300). AF 95% confidence interval is 0.0193. There are 25 homozygotes in GnomAd4. There are 981 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3 link	c.486+8C>T		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1 link	c.582+8C>T		splice_region_variant, intron_variant	Intron 4 of 6		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 link	c.486+8C>T		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2 link	c.84-14039C>T		intron_variant	Intron 1 of 2	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1977

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0213

Gnomad ASJ

AF:

0.00981

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0260

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0122

AC:

3066

AN:

250496

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.0136

Gnomad ASJ exome

AF:

0.00655

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0226

Gnomad NFE exome

AF:

0.0164

Gnomad OTH exome

AF:

0.0142

GnomAD4 exome

AF:

0.0152

AC:

22225

AN:

1460994

Hom.:

179

Cov.:

AF XY:

0.0148

AC XY:

10746

AN XY:

726744

show subpopulations

African (AFR)

AF:

0.00287

AC:

AN:

33480

American (AMR)

AF:

0.0147

AC:

658

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00681

AC:

178

AN:

26134

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.00170

AC:

147

AN:

86218

European-Finnish (FIN)

AF:

0.0222

AC:

1170

AN:

52592

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0172

AC:

19167

AN:

1111992

Other (OTH)

AF:

0.0132

AC:

798

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1379

2758

4137

5516

6895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

718

1436

2154

2872

3590

<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:

0.0130

AC:

1977

AN:

152212

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

981

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00344

AC:

143

AN:

41530

American (AMR)

AF:

0.0212

AC:

325

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00981

AC:

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0260

AC:

276

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1147

AN:

67998

Other (OTH)

AF:

0.0185

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

200

301

401

501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0133

Hom.:

Bravo

AF:

0.0119

TwinsUK

AF:

0.0162

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0116

AC:

1405

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0140

EpiControl

AF:

0.0159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Oct 04, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 17, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jan 05, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21990111, 27535533) -

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLN6: BP4, BS1, BS2 -

Ceroid lipofuscinosis, neuronal, 6A

Pathogenic:1

Translational Research Program on Neuronal Ceroid Lipofuscinosis, Center for the Study of Inborn Errors of Metabolism

Significance:Pathogenic

Review Status:flagged submission

Collection Method:research

Late Infantile NCL -

Inborn genetic diseases

Benign:1

Sep 24, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Agenesis of the corpus callosum with peripheral neuropathy

Benign:1

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous c.486+8C>T variant in CLN6 has been identified in 3 individuals with neuronal ceroid lipofuscinosis, including 2 individuals with no other variants identified in CLN6 (PMID: 21990111), but has been identified in >2% of European (Finnish) chromosomes and 14 homozygotes by ExAC (http://gnomad.broadinstitue.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive neuronal ceroid lipofuscinosis. -

Neuronal ceroid lipofuscinosis

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Benign

2.2

(source)

DANN

Benign

0.82

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0026

PhyloP100

-0.091

PROVEAN

Benign

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.082

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0016

dbscSNV1_RF

Benign

0.048

SpliceAI score (max)

0.010

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