rs786205066

Positions:

• chr15-68211258-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017882.3(CLN6):​c.542+5G>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN6 NM_017882.3 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 7.39

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3	c.542+5G>T		splice_region_variant, intron_variant		ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.638+5G>T		splice_region_variant, intron_variant			NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.542+5G>T		splice_region_variant, intron_variant		1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2	c.84-13630G>T		intron_variant		3		ENSP00000456336.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 6A Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The splice site variant c.542+5G>T in the CLN6 gene has been reported previously in an individual in homozygous state affected with neuronal ceroid lipofuscinosis (Siintola et al., 2005). The c.542+5G>T mutation apparently leads to usage of cryptic donor splice sites in intron 4 in combination with the acceptor splice site of intron 5. This results in the skipping of the exon 5 that precedes the mutated donor splice site. The variant is novel (not in any individuals) in gnomAD Exomes. It is submitted to ClinVar as Pathogenic/ Uncertain significance. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Uncertain significance. -

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 15996215). ClinVar contains an entry for this variant (Variation ID: 4085). This variant has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 15996215). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the CLN6 gene. It does not directly change the encoded amino acid sequence of the CLN6 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205066; hg19: chr15-68503596;