15-68218584-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_017882.3(CLN6):​c.150C>G​(p.Tyr50*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CLN6
NM_017882.3 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 2.37
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-68218584-G-C is Pathogenic according to our data. Variant chr15-68218584-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLN6NM_017882.3 linkc.150C>G p.Tyr50* stop_gained Exon 2 of 7 ENST00000249806.11 NP_060352.1 Q9NWW5-1A0A024R601
CLN6NM_001411068.1 linkc.246C>G p.Tyr82* stop_gained Exon 2 of 7 NP_001397997.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLN6ENST00000249806.11 linkc.150C>G p.Tyr50* stop_gained Exon 2 of 7 1 NM_017882.3 ENSP00000249806.5 Q9NWW5-1
ENSG00000260007ENST00000562767.2 linkc.83+10918C>G intron_variant Intron 1 of 2 3 ENSP00000456336.1 H3BRN7

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251404
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135882
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000397
AC:
58
AN:
1461738
Hom.:
0
Cov.:
31
AF XY:
0.0000426
AC XY:
31
AN XY:
727166
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000540
Hom.:
0
Bravo
AF:
0.0000378

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2Other:1
-
SNPedia
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Nov 15, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although no further clinical details were provided and parental testing was not performed to determine the phase of the three variants (PMID: 21549341); Reported previously as a pathogenic variant in a cohort of patients referred for epilepsy genetic testing; however, no specific clinical information was provided (PMID: 31440721); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31440721, 26075876, 33024953, 21549341) -

Jan 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

CLN6: PVS1, PM2, PM3 -

Neuronal ceroid lipofuscinosis Pathogenic:2
Feb 02, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CLN6 c.150C>G (p.Tyr50X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dec 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). For these reasons, this variant has been classified as Pathogenic. -

Ceroid lipofuscinosis, neuronal, 6A Pathogenic:1
Jul 14, 2017
Counsyl
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.50
CADD
Pathogenic
39
DANN
Uncertain
1.0
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.66
FATHMM_MKL
Uncertain
0.87
D
Vest4
0.74
ClinPred
1.0
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.34
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.34
Position offset: -48

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.

Other links and lift over

dbSNP: rs154774640; hg19: chr15-68510922; API