8-1771113-C-T

Position:

• chr8-1771113-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_018941.4(CLN8):​c.59C>T​(p.Ser20Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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]

KBTBD11-OT1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Protein CLN8 (size 285) in uniprot entity CLN8_HUMAN there are 20 pathogenic changes around while only 7 benign (74%) in NM_018941.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4	c.59C>T	p.Ser20Phe	missense_variant	2/3	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.59C>T	p.Ser20Phe	missense_variant	2/3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.59C>T		non_coding_transcript_exon_variant	2/30	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 20 of the CLN8 protein (p.Ser20Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLN8-related conditions. ClinVar contains an entry for this variant (Variation ID: 1442771). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;T;T;.;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;.;.;.;.;D;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.5	.;M;M;M;M;.;M;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.5	.;N;.;.;.;.;.;.;.
REVEL	Uncertain	0.61
Sift	Benign	0.072	.;T;.;.;.;.;.;.;.
Sift4G	Uncertain	0.027	D;D;.;.;.;.;.;T;.
Polyphen		0.99	.;D;D;D;D;.;D;.;.
Vest4		0.49
MutPred		0.48		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.91
MPC		0.14
ClinPred		0.92	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.74

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

Other links and lift over

dbSNP: rs749651452; hg19: chr8-1719279;