rs796052338

chr16-28477577-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001042432.2(CLN3):c.1256G>A(p.Gly419Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,768 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G419G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 6.69

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 16-28477577-C-T is Pathogenic according to our data. Variant chr16-28477577-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205102.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2	c.1256G>A	p.Gly419Glu	missense_variant	16/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.1256G>A	p.Gly419Glu	missense_variant	16/16	1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74266

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Neuronal ceroid lipofuscinosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 419 of the CLN3 protein (p.Gly419Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with an abnormality of the eye and/or clinical features of retinitis pigmentosa (PMID: 26633542; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 205102). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLN3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

early onset and severe retinal dystrophy Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Laboratory of Genetics in Ophthalmology, Institut Imagine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;.;.;D;.;.;D;D;D;.;D;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;.;.;.;.;.;.;H;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.69	T
Polyphen		1.0	D;D;.;.;D;.;.;.;D;D;D;D;.;D
Vest4		0.82, 0.93, 0.94, 0.93, 0.94, 0.95
MutPred		0.95		Gain of glycosylation at S423 (P = 0.1323);Gain of glycosylation at S423 (P = 0.1323);.;.;.;.;.;.;Gain of glycosylation at S423 (P = 0.1323);.;.;.;.;.;
MVP		0.96
MPC		0.72
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.98

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

Other links and lift over

dbSNP: rs796052338; hg19: chr16-28488898; COSMIC: COSV61107378; COSMIC: COSV61107378;