rs112239768

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_017882.3(CLN6):c.34G>A(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,469,292 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 34)

Exomes 𝑓: 0.016 ( 193 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:14

Conservation

PhyloP100: 0.350

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 -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_017882.3

BP4

Computational evidence support a benign effect (MetaRNN=0.007892162).

BP6

Variant 15-68229551-C-T is Benign according to our data. Variant chr15-68229551-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136802.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0104 (1578/152064) while in subpopulation NFE AF = 0.0179 (1216/67934). AF 95% confidence interval is 0.0171. There are 11 homozygotes in GnomAd4. There are 709 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3 link	c.34G>A	p.Ala12Thr	missense_variant	Exon 1 of 7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1 link	c.180-10901G>A		intron_variant	Intron 1 of 6		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 link	c.34G>A	p.Ala12Thr	missense_variant	Exon 1 of 7	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2 link	c.34G>A	p.Ala12Thr	missense_variant	Exon 1 of 3	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1577

AN:

151956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00649

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00656

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.00816

GnomAD2 exomes

AF:

0.0100

AC:

820

AN:

82002

AF XY:

0.00990

show subpopulations

Gnomad AFR exome

AF:

0.00309

Gnomad AMR exome

AF:

0.00614

Gnomad ASJ exome

AF:

0.00767

Gnomad EAS exome

AF:

0.000273

Gnomad FIN exome

AF:

0.00677

Gnomad NFE exome

AF:

0.0187

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0165

AC:

21701

AN:

1317228

Hom.:

193

Cov.:

AF XY:

0.0159

AC XY:

10304

AN XY:

649704

show subpopulations

African (AFR)

AF:

0.00226

AC:

AN:

26522

American (AMR)

AF:

0.00663

AC:

182

AN:

27446

Ashkenazi Jewish (ASJ)

AF:

0.00735

AC:

169

AN:

22988

East Asian (EAS)

AF:

0.0000354

AC:

AN:

28238

South Asian (SAS)

AF:

0.00289

AC:

212

AN:

73408

European-Finnish (FIN)

AF:

0.00593

AC:

194

AN:

32712

Middle Eastern (MID)

AF:

0.00321

AC:

AN:

4048

European-Non Finnish (NFE)

AF:

0.0192

AC:

20122

AN:

1047446

Other (OTH)

AF:

0.0137

AC:

748

AN:

54420

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1064

2127

3191

4254

5318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.0104

AC:

1578

AN:

152064

Hom.:

Cov.:

AF XY:

0.00954

AC XY:

709

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00332

AC:

138

AN:

41540

American (AMR)

AF:

0.00648

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00656

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0179

AC:

1216

AN:

67934

Other (OTH)

AF:

0.00760

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

159

238

318

397

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:

0.0134

Hom.:

Bravo

AF:

0.0103

ExAC

AF:

0.00293

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLN6: PP3, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 19, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21990111, 29482223) -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:4

Feb 01, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2015

Eurofins Ntd Llc (ga)

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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 16, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuronal ceroid lipofuscinosis

Uncertain:1Benign:2

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 24, 2017

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. -

Ceroid lipofuscinosis, neuronal, 6A

Benign:1

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign, for Ceroid lipofuscinosis, neuronal, 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

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

Benign:1

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CLN6 NM_017882.2 p.Ala12Thr (c.34G>A): This variant has been reported in the literature in at least 2 individuals (1 with neuronal ceroid lipofuscinosis and 1 with cerebellar ataxia) (Kousi 2012 PMID:21990111, Coutelier 2018 PMID:29482223). However, this variant is present in 1.7% (1216/67944) of European alleles including 11 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-68229551-C-T?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are unclear. This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:136802). In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.10

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

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

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.81

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

MetaRNN

Benign

0.0079

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

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.2

.;L;.;.;.;.;.;.

PhyloP100

0.35

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.0

D;N;N;N;.;.;N;.

REVEL

Uncertain

0.53

Sift

Benign

0.059

.;T;D;T;.;.;D;.

Sift4G

Pathogenic

0.0

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

Polyphen

0.030

.;B;.;.;.;.;.;.

Vest4

0.18

MVP

0.81

MPC

0.084

ClinPred

0.017

GERP RS

1.3

PromoterAI

0.074

Neutral

(source)

Varity_R

0.047

gMVP

0.35

Mutation Taster

=88/12

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