16-28487662-C-T

Position:

chr16-28487662-C-T

Variant summary

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

The NM_001042432.2(CLN3):c.374G>A(p.Ser125Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000547 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 4.29

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2 linkuse as main transcript	c.374G>A	p.Ser125Asn	missense_variant, splice_region_variant	6/16	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.374G>A	p.Ser125Asn	missense_variant, splice_region_variant	6/16	1	NM_001042432.2	ENSP00000490105	P1	Q13286-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250136

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135284

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00000547

AC:

AN:

1461222

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

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

Likely pathogenic, no assertion criteria provided

literature only

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

- -

Neuronal ceroid lipofuscinosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces serine with asparagine at codon 125 of the CLN3 protein (p.Ser125Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21499717). ClinVar contains an entry for this variant (Variation ID: 56265). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Benign

0.32

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Benign

0.97

DEOGEN2

Uncertain

0.49

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

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

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

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.23

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

1.5

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

MutationTaster

Benign

0.99

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

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.48

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

REVEL

Benign

0.13

Sift

Benign

1.0

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

Sift4G

Benign

0.56

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

Polyphen

0.33, 0.99, 0.48, 0.60

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

Vest4

0.57, 0.58, 0.58, 0.58, 0.57, 0.55

MutPred

0.44

Loss of glycosylation at S125 (P = 0.0425);Loss of glycosylation at S125 (P = 0.0425);Loss of glycosylation at S125 (P = 0.0425);Loss of glycosylation at S125 (P = 0.0425);.;.;.;Loss of glycosylation at S125 (P = 0.0425);.;Loss of glycosylation at S125 (P = 0.0425);.;.;Loss of glycosylation at S125 (P = 0.0425);.;

MVP

0.78

MPC

0.32

ClinPred

0.43

GERP RS

5.5

Varity_R

0.38

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.52

Position offset: -6

DS_DL_spliceai

0.88

Position offset: 0

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