chr8-1771069-C-G

Variant names:

• chr8-1771069-C-G
• rs374597781
• NM_018941.4:c.15C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018941.4(CLN8):​c.15C>G​(p.Ser5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. S5S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.911
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16332465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN8	NM_018941.4	c.15C>G	p.Ser5Arg	missense_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.15C>G	p.Ser5Arg	missense_variant	Exon 2 of 3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.15C>G		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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Oct 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine with arginine at codon 5 of the CLN8 protein (p.Ser5Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. 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. 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	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.024
DANN	Benign	0.92
DEOGEN2	Benign	0.14	.;T;T;T;T;.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.70	T;.;.;.;.;T;.;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.9	.;M;M;M;M;.;M;.;.
PhyloP100		-0.91
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.61	.;N;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.068	.;T;.;.;.;.;.;.;.
Sift4G	Benign	0.14	T;T;.;.;.;.;.;T;.
Polyphen		0.39	.;B;B;B;B;.;B;.;.
Vest4		0.19
MutPred		0.20		Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);Loss of glycosylation at S5 (P = 0.0112);
MVP		0.65
MPC		0.064
ClinPred		0.13	T
GERP RS		-9.3
Varity_R		0.066
gMVP		0.46
Mutation Taster		=96/4	polymorphism

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: rs374597781; hg19: chr8-1719235;