16-28486639-C-T

Position:

chr16-28486639-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_001042432.2(CLN3):c.472G>A(p.Ala158Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,800 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A158P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001042432.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-28486639-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56273.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2 linkuse as main transcript	c.472G>A	p.Ala158Thr	missense_variant	8/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2 linkuse as main transcript	c.472G>A	p.Ala158Thr	missense_variant	8/16	1	NM_001042432.2	P1	Q13286-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456800

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 20, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2014

p.Ala158Thr (GCT>ACT): c.472 G>A in exon 8 of the CLN3 gene (NM_001042432.1). The Ala158Thr variant 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 6,000 individuals of European and African American ancestry, indicating it is not a common benign variant in these populations. The Ala158Thr variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species in the lumen loop between the third and fourth transmembrane segments of the CLN3 protein and in silico analysis predicts this variant is probably damaging to the protein structure/function. A different amino acid substitution at the same position (Ala158Pro) has been reported in an individual with juvenile neuronal ceroid lipofuscinosis; however, a second mutation in the CLN3 gene was not identified (Kousi et al., 2012) . Based on the currently available information, it is unclear whether Ala158Thr 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

Invitae

Sep 01, 2021

This sequence change replaces alanine with threonine at codon 158 of the CLN3 protein (p.Ala158Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. 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: 205110). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

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

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.89

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

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.5

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.3

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

REVEL

Pathogenic

0.71

Sift

Benign

0.52

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

Sift4G

Benign

0.31

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

Polyphen

0.96, 0.70, 0.95, 0.97

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

Vest4

0.80, 0.81, 0.79, 0.80, 0.78

MutPred

0.80

Loss of catalytic residue at A158 (P = 0.1557);Loss of catalytic residue at A158 (P = 0.1557);Loss of catalytic residue at A158 (P = 0.1557);Loss of catalytic residue at A158 (P = 0.1557);.;.;.;Loss of catalytic residue at A158 (P = 0.1557);.;Loss of catalytic residue at A158 (P = 0.1557);.;.;Loss of catalytic residue at A158 (P = 0.1557);.;.;.;

MVP

0.97

MPC

0.29

ClinPred

0.94

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.67

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