8-1771328-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018941.4(CLN8):c.274C>T(p.His92Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,194 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H92D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (41 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: CLN8 NM_018941.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.29

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.003210485).
• BP6: Variant 8-1771328-C-T is Benign according to our data. Variant chr8-1771328-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-1771328-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1606/152302) while in subpopulation AFR AF= 0.0366 (1519/41554). AF 95% confidence interval is 0.035. There are 41 homozygotes in gnomad4. There are 794 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN8	NM_018941.4	c.274C>T	p.His92Tyr	missense_variant	2/3	ENST00000331222.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN8	ENST00000331222.6	c.274C>T	p.His92Tyr	missense_variant	2/3	1	NM_018941.4	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1587 AN: 152184 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

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: 0.000147

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00280 AC: 703 AN: 251466 Hom.: 13 AF XY: 0.00199 AC XY: 271 AN XY: 135922

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00110 AC: 1603 AN: 1461892 Hom.: 27 Cov.: 32 AF XY: 0.000925 AC XY: 673 AN XY: 727246

Gnomad4 AFR exome AF: 0.0381

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.0105 AC: 1606 AN: 152302 Hom.: 41 Cov.: 32 AF XY: 0.0107 AC XY: 794 AN XY: 74488

Gnomad4 AFR AF: 0.0366

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00178 Hom.: 11

Bravo AF: 0.0117

ESP6500AA AF: 0.0395 AC: 174

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00348 AC: 422

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 25, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Feb 11, 2016

- -

Neuronal ceroid lipofuscinosis 8 Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 03, 2019

- -

Neuronal ceroid lipofuscinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	1.1
Dann	Benign	0.35
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.66	T;.;.;.;.;T;.;T
MetaRNN	Benign	0.0032	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.56	T
Polyphen		0.0	.;B;B;B;B;.;B;.
Vest4		0.20
MVP		0.73
MPC		0.043
ClinPred		0.0019	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.018
gMVP		0.27

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: rs34030778; hg19: chr8-1719494;