8-1771055-A-T

Variant names:

• chr8-1771055-A-T
• rs143730802
• NM_018941.4:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 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 initiator codon 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 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.01
• Publications: 0 publications found

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

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 28 codons. Genomic position: 1771136. Lost 0.095 part of the original CDS.
• PS1: Another start lost variant in NM_018941.4 (CLN8) was described as [Likely_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 rank	MANE	Protein	UniProt
CLN8	NM_018941.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 3	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.1A>T		non_coding_transcript_exon_variant	Exon 2 of 30	5		ENSP00000489726.1

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

Aug 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CLN8 mRNA. The next in-frame methionine is located at codon 28. This variant is not present in population databases (gnomAD no frequency). 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 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. For these reasons, this variant has been classified as Pathogenic. -

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
PhyloP100		6.0
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
Mutation Taster		=48/152	disease causing

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

Other links and lift over

dbSNP: rs143730802; hg19: chr8-1719221;