chr13-76995943-T-G

Position:

chr13-76995943-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000377453.9(CLN5):c.381T>G(p.Thr127=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,614,110 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T127T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 34 hom., cov: 33)

Exomes 𝑓: 0.019 ( 418 hom. )

Consequence

CLN5
ENST00000377453.9 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.284

Variant links:

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]

CLN5 links:

FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

FBXL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 13-76995943-T-G is Benign according to our data. Variant chr13-76995943-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 128783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-76995943-T-G is described in Lovd as [Benign]. Variant chr13-76995943-T-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.284 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN5	NM_006493.4 linkuse as main transcript	c.381T>G	p.Thr127=	synonymous_variant	3/4	ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2 linkuse as main transcript	c.381T>G	p.Thr127=	synonymous_variant	3/5		NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9 linkuse as main transcript	c.381T>G	p.Thr127=	synonymous_variant	3/4	1	NM_006493.4	ENSP00000366673	P1

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2310

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.0691

Gnomad AMR

AF:

0.0241

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.0702

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.00555

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0164

Gnomad OTH

AF:

0.0148

GnomAD3 exomes

AF:

0.0202

AC:

5081

AN:

251484

Hom.:

AF XY:

0.0200

AC XY:

2718

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.0274

Gnomad ASJ exome

AF:

0.0123

Gnomad EAS exome

AF:

0.0657

Gnomad SAS exome

AF:

0.0152

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0190

AC:

27741

AN:

1461792

Hom.:

418

Cov.:

AF XY:

0.0186

AC XY:

13546

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00346

Gnomad4 AMR exome

AF:

0.0272

Gnomad4 ASJ exome

AF:

0.0133

Gnomad4 EAS exome

AF:

0.0858

Gnomad4 SAS exome

AF:

0.0158

Gnomad4 FIN exome

AF:

0.00779

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0195

GnomAD4 genome

AF:

0.0152

AC:

2310

AN:

152318

Hom.:

Cov.:

AF XY:

0.0151

AC XY:

1128

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00397

Gnomad4 AMR

AF:

0.0241

Gnomad4 ASJ

AF:

0.0138

Gnomad4 EAS

AF:

0.0704

Gnomad4 SAS

AF:

0.0180

Gnomad4 FIN

AF:

0.00555

Gnomad4 NFE

AF:

0.0164

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.0176

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.0179

EpiControl

AF:

0.0193

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 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. -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2022	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis 5

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 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. -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuronal ceroid lipofuscinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.7

DANN

Benign

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over