rs137906617

Positions:

chr16-28488643-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000636147.2(CLN3):c.242C>T(p.Pro81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,614,136 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). Synonymous variant affecting the same amino acid position (i.e. P81P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 2 hom. )

Consequence

CLN3
ENST00000636147.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14B:1

Conservation

PhyloP100: 1.95

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01018554).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	5/16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 linkuse as main transcript	c.242C>T	p.Pro81Leu	missense_variant	5/16	1	NM_001042432.2	ENSP00000490105	P1	Q13286-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000588

AC:

148

AN:

251494

Hom.:

AF XY:

0.000743

AC XY:

101

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000352

AC:

515

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

328

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00245

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00131

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000222

Gnomad4 OTH exome

AF:

0.000828

GnomAD4 genome

AF:

0.000341

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000520

Hom.:

Bravo

AF:

0.000302

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 25, 2022	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2022	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -

Neuronal ceroid lipofuscinosis 3

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	May 15, 2020	- -
Uncertain significance, 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, 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. -

Neuronal ceroid lipofuscinosis

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Progressive myoclonic epilepsy type 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 24, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2016

The p.P81L variant (also known as c.242C>T), located in coding exon 4 of the CLN3 gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

.;D;D;.;D;.;T;D;D;.;D;.;T;D

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.82

T;.;.;T;.;T;T;.;T;T;T;T;T;T

MetaRNN

Benign

0.010

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.5

.;M;M;.;.;M;.;M;.;M;.;M;.;.

MutationTaster

Benign

1.0

A;D;D;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-2.0

.;.;N;.;N;N;.;N;.;N;.;N;D;D

REVEL

Uncertain

0.39

Sift

Benign

0.077

.;.;T;.;T;T;.;T;.;T;.;T;D;D

Sift4G

Benign

0.12

.;.;.;T;T;T;.;T;.;T;.;T;.;.

Polyphen

0.97, 0.99, 0.94, 0.94

.;D;D;.;.;.;.;D;.;D;P;P;.;.

Vest4

0.33, 0.33, 0.28, 0.31, 0.34

MVP

0.95

MPC

0.16

ClinPred

0.040

GERP RS

4.4

Varity_R

0.071

gMVP

0.39

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