rs587780900

chr8-1771344-G-TchrNT_187680.1-184001-G-Tchr8-1771344-G-AchrNT_187680.1-184001-G-A

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.290G>T(p.Arg97Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R97H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.223

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 domain TLC (size 200) in uniprot entity CLN8_HUMAN there are 39 pathogenic changes around while only 14 benign (74%) in NM_018941.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026617765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.290G>T	p.Arg97Leu	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.290G>T	p.Arg97Leu	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

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: 0.00000540

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

Aug 24, 2021

This sequence change replaces arginine with leucine at codon 97 of the CLN8 protein (p.Arg97Leu). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CLN8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	0.093
Dann	Benign	0.23
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.52	T;.;.;.;.;T;.;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.027	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
Polyphen		0.0	.;B;B;B;B;.;B;.
Vest4		0.099
MutPred		0.40		Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);Loss of ubiquitination at K95 (P = 0.0653);
MVP		0.39
MPC		0.045
ClinPred		0.026	T
GERP RS		-7.8
Varity_R		0.026
gMVP		0.41

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: rs116605307; hg19: chr8-1719510;