8-1763857-GCAGGGAGCCCGGCTGAGTGGCAGCCCAGGTGAGCGCT-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Strong

The NM_018941.4(CLN8):c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG variant causes a splice donor, splice region, 5 prime UTR, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,210 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 27)

Consequence

CLN8
NM_018941.4 splice_donor, splice_region, 5_prime_UTR, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

Publications

0 publications found

Variant links:

Genes affected

CLN8 (HGNC:2079): (CLN8 transmembrane ER and ERGIC protein) This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. [provided by RefSeq, Jul 2017]

CLN8 links:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

CLN8-AS1 (HGNC:55523): (CLN8 antisense RNA 1)

CLN8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1126597 fraction of the gene. Cryptic splice site detected, with MaxEntScore 10, offset of 3, new splice context is: cagGTgagg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CLN8	NM_018941.4 link	c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	splice_region_variant	Exon 1 of 3	ENST00000331222.6	NP_061764.2	Q9UBY8A0A024QZ57
CLN8	NM_018941.4 link	c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	splice_donor_variant, splice_region_variant, 5_prime_UTR_variant, intron_variant	Exon 1 of 3	ENST00000331222.6	NP_061764.2	Q9UBY8A0A024QZ57
CLN8	NM_018941.4 link	c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	non_coding_transcript_variant		ENST00000331222.6	NP_061764.2	Q9UBY8A0A024QZ57

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLN8	ENST00000331222.6 link	c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	splice_region_variant	Exon 1 of 3	1	NM_018941.4	ENSP00000328182.4	Q9UBY8
KBTBD11-OT1	ENST00000635855.1 link	n.-195_-159delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	non_coding_transcript_exon_variant	Exon 1 of 30	5		ENSP00000489726.1	A0A1B0GTJ5
KBTBD11-OT1	ENST00000635855.1 link	n.-195_-159delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	5_prime_UTR_variant	Exon 1 of 30	5		ENSP00000489726.1	A0A1B0GTJ5
CLN8	ENST00000331222.6 link	c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	splice_donor_variant, splice_region_variant, 5_prime_UTR_variant, intron_variant	Exon 1 of 3	1	NM_018941.4	ENSP00000328182.4	Q9UBY8
CLN8	ENST00000331222.6 link	c.-139_-124+21delCTGAGTGGCAGCCCAGGTGAGCGCTCAGGGAGCCCGG	non_coding_transcript_variant		1	NM_018941.4	ENSP00000328182.4	Q9UBY8
KBTBD11-OT1	ENST00000635855.1 link	n.-207_-171delCAGGGAGCCCGGCTGAGTGGCAGCCCAGGTGAGCGCT	upstream_gene_variant		5		ENSP00000489726.1	A0A1B0GTJ5

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151210

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73820

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41180

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5022

South Asian (SAS)

AF:

0.00

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67716

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Feb 16, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the CLN8 gene. The c. -139_-124+21del37 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. No data are available from control populations to assess the frequency of this variant. This variant spans the 3' end of the noncoding exon 1 and the donor site of intron 2. Several in-silico splice prediction models predict that c. -139_-124+21del37 variant may destroy the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Additionally, to our knowledge, splice and regulatory variants have not been reported in CLN8 in association with NCL (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Splicing

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

Publications

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8-1763857-GCAGGGAGCCCGGCTGAGTGGCAGCCCAGGTGAGCGCT-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over