Variant 8-1771142-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_018941.4(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
NM_018941.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.47

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_018941.4

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 id is 2806.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-1771142-G-C is described in UniProt as null. Variant chr8-1771142-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4 linkuse as main transcript	c.88G>C	p.Ala30Pro	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6 linkuse as main transcript	c.88G>C	p.Ala30Pro	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 8

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

.;D;D;D;D;.;D;.;.

Eigen

Benign

0.053

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

T;.;.;.;.;T;.;T;T

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.68

MutationAssessor

Uncertain

2.5

.;M;M;M;M;.;M;.;.

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.8

.;D;.;.;.;.;.;.;.

REVEL

Pathogenic

0.70

Sift

Benign

0.059

.;T;.;.;.;.;.;.;.

Sift4G

Benign

0.11

T;T;.;.;.;.;.;T;.

Polyphen

0.96

.;P;P;P;P;.;P;.;.

Vest4

0.93

MutPred

0.67

Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over