Genetic Variant CLN3:p.Glu257Asp (chr16-28484025-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042432.2(CLN3):c.771G>C(p.Glu257Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E257E) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -0.125

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19791394).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.771G>C	p.Glu257Asp	missense_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.771G>C	p.Glu257Asp	missense_variant	Exon 10 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458354

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725030

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3

Uncertain:3

Dec 20, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis

Uncertain:2

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with aspartic acid at codon 257 of the CLN3 protein (p.Glu257Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CLN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 497479). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

not provided

Uncertain:1

Oct 13, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.27

CADD

Benign

1.3

DANN

Benign

0.82

DEOGEN2

Uncertain

0.54

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

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.79

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

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.20

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

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.4

.;L;L;.;.;.;.;.;.;L;.;L;.;.;.;.;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.35

.;.;N;.;.;N;N;N;.;N;.;N;.;.;N;.;N;.;N

REVEL

Uncertain

0.34

Sift

Benign

0.23

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

Sift4G

Benign

0.17

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

Polyphen

0.043, 0.49, 0.20, 0.24, 0.73, 0.010

.;B;B;.;.;P;.;.;.;B;P;B;B;.;P;.;B;.;.

Vest4

0.29, 0.31, 0.29, 0.30, 0.30, 0.37

MutPred

0.51

Loss of glycosylation at P259 (P = 0.0891);Loss of glycosylation at P259 (P = 0.0891);Loss of glycosylation at P259 (P = 0.0891);Loss of glycosylation at P259 (P = 0.0891);.;.;.;.;.;Loss of glycosylation at P259 (P = 0.0891);.;Loss of glycosylation at P259 (P = 0.0891);.;.;.;.;.;.;.;

MVP

0.89

MPC

0.23

ClinPred

0.29

GERP RS

-0.16

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.083

gMVP

0.24

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