rs1554448978

Positions:

• chr8-1771160-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_018941.4(CLN8):​c.106T>A​(p.Leu36Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.149

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.17546734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4	c.106T>A	p.Leu36Met	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.106T>A	p.Leu36Met	missense_variant	2/3	1	NM_018941.4	ENSP00000328182	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152068 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH 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

Oct 13, 2022

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 36 of the CLN8 protein (p.Leu36Met). 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: 527756). 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	0.15
BayesDel_addAF	Benign	0.0095	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T;T;T;T;.;T;.;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.73	T;.;.;.;.;T;.;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	.;M;M;M;M;.;M;.;.
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.090	.;N;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.082	.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.;.;T;.
Polyphen		0.52	.;P;P;P;P;.;P;.;.
Vest4		0.27
MutPred		0.35		Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);Loss of catalytic residue at L36 (P = 0.1884);
MVP		0.79
MPC		0.046
ClinPred		0.20	T
GERP RS		0.042
Varity_R		0.056
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: rs1554448978; hg19: chr8-1719326;