16-28484028-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001042432.2(CLN3):c.768C>T(p.Thr256Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000361 in 1,610,850 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00094 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

CLN3
NM_001042432.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: -3.23

Variant links:

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

CLN3 links:

ENSG00000261832 (HGNC:):

ENSG00000261832 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-28484028-G-A is Benign according to our data. Variant chr16-28484028-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93505.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=3}. Variant chr16-28484028-G-A is described in Lovd as [Benign]. Variant chr16-28484028-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00094 (143/152198) while in subpopulation AFR AF= 0.00238 (99/41532). AF 95% confidence interval is 0.002. There are 1 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.768C>T	p.Thr256Thr	synonymous_variant	Exon 10 of 16	ENST00000636147.2	NP_001035897.1	Q13286-1A0A024QZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 link	c.768C>T	p.Thr256Thr	synonymous_variant	Exon 10 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000655

AC:

160

AN:

244296

Hom.:

AF XY:

0.000659

AC XY:

AN XY:

132096

show subpopulations

Gnomad AFR exome

AF:

0.00245

Gnomad AMR exome

AF:

0.000294

Gnomad ASJ exome

AF:

0.00778

Gnomad EAS exome

AF:

0.000495

Gnomad SAS exome

AF:

0.000101

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.000670

GnomAD4 exome

AF:

0.000301

AC:

439

AN:

1458652

Hom.:

Cov.:

AF XY:

0.000285

AC XY:

207

AN XY:

725222

show subpopulations

Gnomad4 AFR exome

AF:

0.00269

Gnomad4 AMR exome

AF:

0.000316

Gnomad4 ASJ exome

AF:

0.00746

Gnomad4 EAS exome

AF:

0.000303

Gnomad4 SAS exome

AF:

0.0000469

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000621

Gnomad4 OTH exome

AF:

0.000863

GnomAD4 genome

AF:

0.000940

AC:

143

AN:

152198

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00864

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000916

Hom.:

Bravo

AF:

0.00105

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Sep 22, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 14, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 3

Uncertain:1Benign:2

May 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 09, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 08, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.35

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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