8-1771061-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_018941.4(CLN8):c.7C>T(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P3P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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 Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain Protein CLN8 (size 285) in uniprot entity CLN8_HUMAN there are 49 pathogenic changes around while only 20 benign (71%) in NM_018941.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050497115).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.7C>T	p.Pro3Ser	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.7C>T	p.Pro3Ser	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Invitae

Jul 31, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 3 of the CLN8 protein (p.Pro3Ser). 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: 969683). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN8 protein function. 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	0.070
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	3.9
Dann	Benign	0.37
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.58	T;.;.;.;.;T;.;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.050	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
Sift4G	Benign	0.46	T;T;.;.;.;.;.;T;.
Polyphen		0.0010	.;B;B;B;B;.;B;.;.
Vest4		0.14
MutPred		0.17		Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);Loss of catalytic residue at P3 (P = 8e-04);
MVP		0.77
MPC		0.039
ClinPred		0.013	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.035
gMVP		0.53

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: rs767218890; hg19: chr8-1719227;