rs149692285

Positions:

Variant summary

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

The NM_017882.3(CLN6):c.486+8C>T variant causes a splice region, intron 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. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 32)

Exomes 𝑓: 0.015 ( 179 hom. )

Consequence

CLN6
NM_017882.3 splice_region, intron

Scores

Splicing: ADA: 0.001581

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:12

Conservation

PhyloP100: -0.0910

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:

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=0.0026243627).

BP6

Variant 15-68211667-G-A is Benign according to our data. Variant chr15-68211667-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128786.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=9}. Variant chr15-68211667-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN6	NM_017882.3 linkuse as main transcript	c.486+8C>T		splice_region_variant, intron_variant		ENST00000249806.11
CLN6	NM_001411068.1 linkuse as main transcript	c.582+8C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11 linkuse as main transcript	c.486+8C>T		splice_region_variant, intron_variant		1	NM_017882.3	P1	Q9NWW5-1

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

GnomAD3 exomes

AF:

0.0122

AC:

3066

AN:

250496

Hom.:

AF XY:

0.0122

AC XY:

1648

AN XY:

135346

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 SAS exome

AF:

0.00154

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

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.0147

Gnomad4 ASJ exome

AF:

0.00681

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00170

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.0172

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.0130

AC:

1977

AN:

152212

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

981

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00344

Gnomad4 AMR

AF:

0.0212

Gnomad4 ASJ

AF:

0.00981

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0260

Gnomad4 NFE

AF:

0.0169

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.0106

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 01, 2020	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2018	This variant is associated with the following publications: (PMID: 21990111, 27535533) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CLN6: BP4, BS1, BS2 -

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). 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. -

Ceroid lipofuscinosis, neuronal, 6A

Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

Late Infantile NCL -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2018

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

Benign, criteria provided, single submitter

research

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

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Benign

2.2

DANN

Benign

0.82

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0026

MutationTaster

Benign

1.0

D;D;N;N;N;N

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

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

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