rs386833723

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001042432.2(CLN3):c.472G>C(p.Ala158Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,608,962 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 4.54

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.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.472G>C	p.Ala158Pro	missense_variant	Exon 8 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.472G>C	p.Ala158Pro	missense_variant	Exon 8 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00000417

AC:

AN:

239584

Hom.:

AF XY:

0.00000773

AC XY:

AN XY:

129442

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000297

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456798

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724114

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

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

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3

Pathogenic:1

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Uncertain:1

Feb 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CLN3 c.472G>C (p.Ala158Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 239584 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.472G>C has been reported in the literature in at least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) who was submitted to the NCL database, however no further genotype information was provided (Kousi_2012). This report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). At least two publications report experimental evidence evaluating an impact on protein function. Specifically, one study using the Schizosaccharomyces pombe model, demonstrated that the variant in the yeast ortholog prevented the encoded protein from exiting from the endoplasmic reticulum, suggesting the variant disrupts protein folding and, in turn, could lead to degradation. In addition, it was shown that the variant could not fully rescue any of the marker phenotypes (vacuole size, septation, monopolarity, or curving) in the model system (example: Haines_2009). Another study, using CLN3 KO HeLa cells cotransfected with the GFP-CLN3 missense variant, found that the variant mislocalized to the cytosol (example: Scotto Rosato_2022). However, these findings do not allow for strong conclusions to be made about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 19132115, 35929194). ClinVar contains an entry for this variant (Variation ID: 56273). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

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

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

.;H;H;.;.;.;.;H;.;H;.;.;H;.;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.6

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

REVEL

Pathogenic

0.91

Sift

Uncertain

0.010

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0, 1.0, 1.0

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

Vest4

0.94, 0.94, 0.93, 0.94, 0.93

MutPred

0.91

Loss of catalytic residue at A158 (P = 0.0401);Loss of catalytic residue at A158 (P = 0.0401);Loss of catalytic residue at A158 (P = 0.0401);Loss of catalytic residue at A158 (P = 0.0401);.;.;.;Loss of catalytic residue at A158 (P = 0.0401);.;Loss of catalytic residue at A158 (P = 0.0401);.;.;Loss of catalytic residue at A158 (P = 0.0401);.;.;.;

MVP

0.97

MPC

0.71

ClinPred

0.99

GERP RS

5.8

Varity_R

0.98

gMVP

0.94

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