8-1771428-A-C

Position:

• chr8-1771428-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_018941.4(CLN8):​c.374A>C​(p.Asn125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 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. N125S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain TLC (size 200) in uniprot entity CLN8_HUMAN there are 17 pathogenic changes around while only 5 benign (77%) in NM_018941.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-1771428-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4	c.374A>C	p.Asn125Thr	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.374A>C	p.Asn125Thr	missense_variant	2/3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.374A>C		non_coding_transcript_exon_variant	2/30	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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2014

p.Asn125Thr (AAC>ACC): c.374 A>C in exon 2 of the CLN8 gene (NM_018941.3)A variant of unknown significance has been identified in the CLN8 gene. The N125T variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. A different amino acid substitution at the same position (N125S) has been reported as possibly disease causing; however segregation analysis and functional studies have not been performed to support this conclusion (Kousi et al., 2012). N125T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N125T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs between transmembrane domains 3 and 4 at a position that is conserved in mammals; however in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The finding of a single missense variant of unknown clinical significance makes the molecular diagnosis inconclusive. The variant is found in EPILEPSY panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	9.5
DANN	Benign	0.77
DEOGEN2	Uncertain	0.44	.;T;T;T;T;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.81	T;.;.;.;.;T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.3	.;M;M;M;M;.;M;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.61	.;N;.;.;.;.;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.024	.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	.;D;.;.;.;.;.;D
Polyphen		0.56	.;P;P;P;P;.;P;.
Vest4		0.55
MutPred		0.79		Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);Gain of glycosylation at S124 (P = 0.0985);
MVP		0.87
MPC		0.058
ClinPred		0.12	T
GERP RS		-0.080
Varity_R		0.043
gMVP		0.37

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: rs142269885; hg19: chr8-1719594;