rs9565308

Positions:

• chr13-76992279-C-T

Variant summary

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

The NM_006493.4(CLN5):​c.173+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.043 in 1,437,784 control chromosomes in the GnomAD database, including 1,834 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (221 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1613 hom.)
• Consequence: CLN5 NM_006493.4 splice_region, intron
• Scores: Splicing: ADA: 0.00004547
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.562

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]

ENSG00000283208 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 13-76992279-C-T is Benign according to our data. Variant chr13-76992279-C-T is described in ClinVar as [Benign]. Clinvar id is 128781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-76992279-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN5	NM_006493.4	c.173+8C>T		splice_region_variant, intron_variant		ENST00000377453.9	NP_006484.2
CLN5	NM_001366624.2	c.173+8C>T		splice_region_variant, intron_variant			NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9	c.173+8C>T		splice_region_variant, intron_variant		1	NM_006493.4	ENSP00000366673.5
ENSG00000283208	ENST00000638147.2	c.173+8C>T		splice_region_variant, intron_variant		5		ENSP00000490953.2

Frequencies

GnomAD3 genomes AF: 0.0390 AC: 5805 AN: 149034 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0989

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0562

Gnomad FIN AF: 0.0406

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0335

GnomAD3 exomes AF: 0.0688 AC: 10355 AN: 150580 Hom.: 519 AF XY: 0.0632 AC XY: 5251 AN XY: 83084

Gnomad AFR exome AF: 0.0107

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.0279

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0360

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0435 AC: 56000 AN: 1288626 Hom.: 1613 Cov.: 35 AF XY: 0.0434 AC XY: 27661 AN XY: 636954

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.168

Gnomad4 ASJ exome AF: 0.0339

Gnomad4 EAS exome AF: 0.159

Gnomad4 SAS exome AF: 0.0533

Gnomad4 FIN exome AF: 0.0536

Gnomad4 NFE exome AF: 0.0358

Gnomad4 OTH exome AF: 0.0462

GnomAD4 genome AF: 0.0390 AC: 5812 AN: 149158 Hom.: 221 Cov.: 32 AF XY: 0.0413 AC XY: 3009 AN XY: 72834

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.0993

Gnomad4 ASJ AF: 0.0322

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.0561

Gnomad4 FIN AF: 0.0406

Gnomad4 NFE AF: 0.0334

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0332 Hom.: 28

Bravo AF: 0.0427

Asia WGS AF: 0.0970 AC: 337 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2022	- -

Neuronal ceroid lipofuscinosis 5 Benign:2

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

not provided Benign:2

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

Neuronal ceroid lipofuscinosis Benign:2

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

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Benign:1

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	-0.69
CADD	Benign	6.8
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000045
dbscSNV1_RF	Benign	0.0020
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: rs9565308; hg19: chr13-77566414;