13-76992103-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006493.4(CLN5):c.5C>T(p.Ala2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000385 in 1,611,760 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.262

Genes affected

CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056524277).
• BP6: Variant 13-76992103-C-T is Benign according to our data. Variant chr13-76992103-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205125.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, Benign=1}. Variant chr13-76992103-C-T is described in Lovd as [Benign]. Variant chr13-76992103-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4	c.5C>T	p.Ala2Val	missense_variant	1/4	ENST00000377453.9
CLN5	NM_001366624.2	c.5C>T	p.Ala2Val	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.5C>T	p.Ala2Val	missense_variant	1/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152230 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000694 AC: 163 AN: 234904 Hom.: 0 AF XY: 0.000719 AC XY: 93 AN XY: 129384

Gnomad AFR exome AF: 0.0000705

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000245

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000374 AC: 546 AN: 1459530 Hom.: 2 Cov.: 35 AF XY: 0.000402 AC XY: 292 AN XY: 726102

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000972

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152230 Hom.: 2 Cov.: 33 AF XY: 0.000444 AC XY: 33 AN XY: 74366

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.0156

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.000997 Hom.: 1

Bravo AF: 0.000427

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000587 AC: 5

ExAC AF: 0.000548 AC: 66

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2016	- -

Neuronal ceroid lipofuscinosis 5 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Neuronal ceroid lipofuscinosis Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2018

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	14
Dann	Uncertain	1.0
DEOGEN2	Benign	0.062	T;T;T;T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.58	T;.;T;.;.;.
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.0057	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.74	T
Polyphen		0.086	.;.;B;.;.;.
MVP		0.40
MPC		0.52
ClinPred		0.047	T
GERP RS		1.9
Varity_R		0.057

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: rs146993892; hg19: chr13-77566238; COSMIC: COSV66284048; COSMIC: COSV66284048;