chr8-1771055-A-T

Position:

• chr8-1771055-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_018941.4(CLN8):​c.1A>T​(p.Met1?) variant causes a start lost change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN8 NM_018941.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_018941.4 (CLN8) was described as [Pathogenic] in ClinVar as 487522
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-1771055-A-T is Pathogenic according to our data. Variant chr8-1771055-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 2749928.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.1A>T	p.Met1?	start_lost	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.1A>T	p.Met1?	start_lost	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 04, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the CLN8 protein in which other variant(s) (p.Arg24Gly) have been determined to be pathogenic (PMID: 10508524, 10861296, 15160397, 16828266). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Disruption of the initiator codon has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis type 8 (PMID: 30741402, 31069529). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CLN8 mRNA. The next in-frame methionine is located at codon 28. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.11	.;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	0.010	.;N;.;.;.;.;.;.;.
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;.;.;.;.;.;D;.
Polyphen		0.99	.;D;D;D;D;.;D;.;.
Vest4		0.93
MutPred		0.99		Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);Loss of phosphorylation at S5 (P = 0.2097);
MVP		0.96
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.82
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-1719221;