rs149692285

Variant names:

• chr15-68211667-G-A
• rs149692285
• NM_017882.3:c.486+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-68211667-G-A
• chr15-68211667-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 Likely benign (★★).

• 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: -0.0910

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]

ENSG00000260007 (HGNC:):

ACMG classification

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 [Likely_benign]. Clinvar id is 128786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED 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	c.486+8C>T		splice_region_variant, intron_variant	Intron 4 of 6	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	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	c.486+8C>T		splice_region_variant, intron_variant	Intron 4 of 6	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2	c.84-14039C>T		intron_variant	Intron 1 of 2	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1977 AN: 152094 Hom.: 25 Cov.: 32

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

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.: 31 AF XY: 0.0148 AC XY: 10746 AN XY: 726744

Gnomad4 AFR exome AF: 0.00287 AC: 96 AN: 33480

Gnomad4 AMR exome AF: 0.0147 AC: 658 AN: 44722

Gnomad4 ASJ exome AF: 0.00681 AC: 178 AN: 26134

Gnomad4 EAS exome AF: 0.0000756 AC: 3 AN: 39700

Gnomad4 SAS exome AF: 0.00170 AC: 147 AN: 86218

Gnomad4 FIN exome AF: 0.0222 AC: 1170 AN: 52592

Gnomad4 NFE exome AF: 0.0172 AC: 19167 AN: 1111992

Gnomad4 Remaining exome AF: 0.0132 AC: 798 AN: 60388

GnomAD4 genome AF: 0.0130 AC: 1977 AN: 152212 Hom.: 25 Cov.: 32 AF XY: 0.0132 AC XY: 981 AN XY: 74408

Gnomad4 AFR AF: 0.00344 AC: 0.00344329 AN: 0.00344329

Gnomad4 AMR AF: 0.0212 AC: 0.0212418 AN: 0.0212418

Gnomad4 ASJ AF: 0.00981 AC: 0.00980958 AN: 0.00980958

Gnomad4 EAS AF: 0.000193 AC: 0.000193424 AN: 0.000193424

Gnomad4 SAS AF: 0.00166 AC: 0.001657 AN: 0.001657

Gnomad4 FIN AF: 0.0260 AC: 0.0260279 AN: 0.0260279

Gnomad4 NFE AF: 0.0169 AC: 0.0168681 AN: 0.0168681

Gnomad4 OTH AF: 0.0185 AC: 0.0184834 AN: 0.0184834

Alfa AF: 0.0133 Hom.: 27

Bravo AF: 0.0119

TwinsUK AF: 0.0162 AC: 60

ALSPAC AF: 0.0182 AC: 70

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0116 AC: 1405

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Likely 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. -

Oct 04, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

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) -

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 -

Oct 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 05, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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: no assertion criteria provided

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
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	2.2
DANN	Benign	0.82
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0026	T
PROVEAN	Benign	0.83	N
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.082
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs149692285; hg19: chr15-68504005; COSMIC: COSV106331001; COSMIC: COSV106331001;