chr13-76992023-A-G

Position:

• chr13-76992023-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000636183.2(CLN5):​c.-76A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,606,282 control chromosomes in the GnomAD database, including 3,068 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (785 hom., cov: 33)
  • Exomes 𝑓: 0.045 (2283 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.43

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 13-76992023-A-G is Benign according to our data. Variant chr13-76992023-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 95398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-76992023-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000636183.2	c.-76A>G		5_prime_UTR_variant	1/4	1		ENSP00000490181	P1
CLN5	ENST00000485938.4			upstream_gene_variant		2		ENSP00000482959
CLN5	ENST00000636780.2			upstream_gene_variant		5		ENSP00000489809

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12477 AN: 152126 Hom.: 788 Cov.: 33

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.138

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0337

Gnomad OTH AF: 0.0684

GnomAD3 exomes AF: 0.0717 AC: 15940 AN: 222188 Hom.: 850 AF XY: 0.0638 AC XY: 7878 AN XY: 123470

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.169

Gnomad ASJ exome AF: 0.0410

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.0534

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0583

GnomAD4 exome AF: 0.0450 AC: 65399 AN: 1454040 Hom.: 2283 Cov.: 35 AF XY: 0.0441 AC XY: 31855 AN XY: 723108

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.162

Gnomad4 ASJ exome AF: 0.0412

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.0524

Gnomad4 FIN exome AF: 0.0356

Gnomad4 NFE exome AF: 0.0336

Gnomad4 OTH exome AF: 0.0501

GnomAD4 genome AF: 0.0821 AC: 12499 AN: 152242 Hom.: 785 Cov.: 33 AF XY: 0.0827 AC XY: 6156 AN XY: 74444

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.0476

Gnomad4 EAS AF: 0.138

Gnomad4 SAS AF: 0.0526

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.0337

Gnomad4 OTH AF: 0.0695

Alfa AF: 0.0325 Hom.: 46

Bravo AF: 0.0924

Asia WGS AF: 0.105 AC: 364 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 22. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
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. -

Neuronal ceroid lipofuscinosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.4
DANN	Benign	0.68

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: rs7987664; hg19: chr13-77566158; COSMIC: COSV66284915; COSMIC: COSV66284915;