rs121908080

chr15-68211697-TTGA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_017882.3(CLN6):c.461_463del(p.Ile154del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I154I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CLN6 NM_017882.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: 8.79

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_017882.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_017882.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 15-68211697-TTGA-T is Pathogenic according to our data. Variant chr15-68211697-TTGA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN6	NM_017882.3	c.461_463del	p.Ile154del	inframe_deletion	4/7	ENST00000249806.11
CLN6	NM_001411068.1	c.557_559del	p.Ile186del	inframe_deletion	4/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11	c.461_463del	p.Ile154del	inframe_deletion	4/7	1	NM_017882.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251134 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461604 Hom.: 0 AF XY: 0.00000413 AC XY: 3 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74294

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 6A Pathogenic:4 Other: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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 18, 2017	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 11, 2022	- -

Neuronal ceroid lipofuscinosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2023	Variant summary: CLN6 c.461_463delTCA (p.Ile154del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 251134 control chromosomes (gnomAD). c.461_463delTCA has been reported in the literature in several homozygous and compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Teixeira_2003, Bouhouche_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated decreased half-life for the variant protein (Kurze_2010). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This variant, c.461_463del, results in the deletion of 1 amino acid(s) of the CLN6 protein (p.Ile154del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs121908080, gnomAD 0.003%). This variant has been observed in individuals with CLN6-related conditions (PMID: 11727201, 12673792, 21990111). ClinVar contains an entry for this variant (Variation ID: 4083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CLN6 function (PMID: 20020536). For these reasons, this variant has been classified as Pathogenic. -

Ceroid lipofuscinosis, neuronal, 6A;C5561927:Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 23, 2021

- -

See cases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 26, 2019

ACMG classification criteria: PS4, PM2, PM3, PM4, PP3 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121908080; hg19: chr15-68504035;