rs138037471

Positions:

• chr13-76992185-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006493.4(CLN5):​c.87C>G​(p.Ala29=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,605,390 control chromosomes in the GnomAD database, including 914 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. A29A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (83 hom., cov: 33)
  • Exomes 𝑓: 0.032 (831 hom.)
• Consequence: CLN5 NM_006493.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.426

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 13-76992185-C-G is Benign according to our data. Variant chr13-76992185-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 95396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-76992185-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.426 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0245 (3726/152270) while in subpopulation AMR AF= 0.0352 (538/15298). AF 95% confidence interval is 0.0334. There are 83 homozygotes in gnomad4. There are 1818 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 83 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN5	NM_006493.4	c.87C>G	p.Ala29=	synonymous_variant	1/4	ENST00000377453.9
CLN5	NM_001366624.2	c.87C>G	p.Ala29=	synonymous_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN5	ENST00000377453.9	c.87C>G	p.Ala29=	synonymous_variant	1/4	1	NM_006493.4	P1

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3732 AN: 152156 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.00687

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0239 AC: 5352 AN: 223732 Hom.: 100 AF XY: 0.0240 AC XY: 2963 AN XY: 123434

Gnomad AFR exome AF: 0.00583

Gnomad AMR exome AF: 0.0201

Gnomad ASJ exome AF: 0.0644

Gnomad EAS exome AF: 0.0000577

Gnomad SAS exome AF: 0.00782

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0334

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0316 AC: 45973 AN: 1453120 Hom.: 831 Cov.: 36 AF XY: 0.0311 AC XY: 22463 AN XY: 722840

Gnomad4 AFR exome AF: 0.00511

Gnomad4 AMR exome AF: 0.0202

Gnomad4 ASJ exome AF: 0.0648

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00827

Gnomad4 FIN exome AF: 0.0212

Gnomad4 NFE exome AF: 0.0356

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0245 AC: 3726 AN: 152270 Hom.: 83 Cov.: 33 AF XY: 0.0244 AC XY: 1818 AN XY: 74454

Gnomad4 AFR AF: 0.00685

Gnomad4 AMR AF: 0.0352

Gnomad4 ASJ AF: 0.0657

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.0194

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0331 Hom.: 37

Bravo AF: 0.0252

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	Jul 12, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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. -

Neuronal ceroid lipofuscinosis 5 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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

May 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 12, 2017

- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.8
DANN	Benign	0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs138037471; hg19: chr13-77566320; COSMIC: COSV66283623; COSMIC: COSV66283623;