Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The ENST00000331222.6(CLN8):c.88G>C(p.Ala30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A30S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CLN8
ENST00000331222.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.47

Publications

11 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 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 8
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
neuronal ceroid lipofuscinosis 8 northern epilepsy variant
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
autism spectrum disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

CLN8 links:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in ENST00000331222.6

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

PP5

Variant 8-1771142-G-C is Pathogenic according to our data. Variant chr8-1771142-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2806.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000331222.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN8	NM_018941.4	MANE Select	c.88G>C	p.Ala30Pro	missense	Exon 2 of 3	NP_061764.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLN8	ENST00000331222.6	TSL:1 MANE Select	c.88G>C	p.Ala30Pro	missense	Exon 2 of 3	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	TSL:5	n.88G>C		non_coding_transcript_exon	Exon 2 of 30	ENSP00000489726.1
CLN8	ENST00000519254.2	TSL:5	c.88G>C	p.Ala30Pro	missense	Exon 2 of 3	ENSP00000490016.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

Eigen

Benign

0.053

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

PhyloP100

3.5

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.70

Sift

Benign

0.059

Sift4G

Benign

0.11

Polyphen

0.96

Vest4

0.93

MutPred

0.67

Gain of sheet (P = 0.0477)

MVP

0.93

MPC

0.24

ClinPred

0.92

GERP RS

4.2

Varity_R

0.59

gMVP

0.88

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over