rs776443981

Positions:

chr16-28477608-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001042432.2(CLN3):c.1225A>G(p.Met409Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.93

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a mutagenesis_site Does not affect lysosomal targeting; when associated with A-419. Loss of lysosomal targeting; when associated with A-253 and A-254. Loss of lysosomal targeting; when associated with 242-A--A-244 and A-419. Does not affect interaction with CLN5; when associated with A-419. Does not affect interaction with CLN5; when associated with A-253; A-254 and A-419. Loss of lysosomal targeting; when associated with A-253; A-254 and A-419. Loss of lysosomal localization in AP3D1 or AP1G1 deficient cells; when associated with A-419. (size 0) in uniprot entity CLN3_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.1225A>G	p.Met409Val	missense_variant	16/16	ENST00000636147.2	NP_001035897.1	Q13286-1A0A024QZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 link	c.1225A>G	p.Met409Val	missense_variant	16/16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1
ENSG00000261832	ENST00000637378.1 link	c.228+4497A>G		intron_variant		5		ENSP00000490831.1		A0A1B0GW90

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250566

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461752

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2014

p.Met409Val (ATG>GTG): c.1225 A>G in exon 16 of the CLN3 gene (NM_001042432.1). The Met409Val missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Met409Val variant alters a well conserved region across species in the cytoplasmic C-terminus region of the CLN3 protein and a nearby missense mutation has been reported in this region of the CLN3 protein in association with neuronal ceroid lipofuscinosis (Kousi et al., 2012). In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. However, this variant is a conservative substitution of one uncharged non-polar amino acid for another. Therefore, based on the currently available information, it is unclear whether Met409Val is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). -

Neuronal ceroid lipofuscinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 18, 2022

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 409 of the CLN3 protein (p.Met409Val). This variant is present in population databases (rs776443981, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 33507216). ClinVar contains an entry for this variant (Variation ID: 205101). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neuronal ceroid lipofuscinosis 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;D;.;.;D;.;.;D;D;D;.;D;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

.;.;D;.;.;D;D;D;.;D;D;D;.;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.5

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

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.1

.;D;.;.;D;D;D;.;D;.;D;.;.;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0040

.;D;.;.;D;D;D;.;D;.;D;.;.;D

Sift4G

Uncertain

0.053

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

Polyphen

0.99

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

Vest4

0.49, 0.66, 0.64, 0.67, 0.66, 0.73

MutPred

0.73

Loss of disorder (P = 0.1129);Loss of disorder (P = 0.1129);.;.;.;.;.;.;Loss of disorder (P = 0.1129);.;.;.;.;.;

MVP

0.91

MPC

0.52

ClinPred

0.78

GERP RS

3.9

Varity_R

0.69

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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