rs386833731

Positions:

• chr16-28486459-C-A
• chr16-28486459-C-G
• chr16-28486459-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_001042432.2(CLN3):​c.565G>T​(p.Gly189Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,042 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G189R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.52

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity CLN3_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 chr16-28486459-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 16-28486459-C-A is Pathogenic according to our data. Variant chr16-28486459-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 886715.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr16-28486459-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.565G>T	p.Gly189Trp	missense_variant	9/16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.565G>T	p.Gly189Trp	missense_variant	9/16	1	NM_001042432.2	ENSP00000490105	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461042 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726776

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:1 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Lab, NIMHANS, National Institute of Mental Health and Neuro Sciences	Oct 17, 2023	The missense variant NM_001042432.2:c.565G>T causes a change at the same amino acid residue as a previously established pathogenic variant. The NP_001035897.1:p.Gly189Trp variant is previously reported to ClinVar (Accession:VCV000886715.5 ) as a variant of uncertain significance. The NP_001035897.1:p.Gly189Trp variant is novel (not in any individuals) in 1000 Genomes as well as in our inhouse database. Although the variant is present at 0.0000% in gnomAD, it has the flag "RF" and may not represent the true population frequency. There is a large physicochemical difference between glycine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. 2 variants within 6 amino acid positions of the variant p.Gly189Trp have been shown to be pathogenic, while none have been shown to be benign. The p.Gly189Trp missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 189 of CLN3 is conserved in all mammalian species. The nucleotide c.565 in CLN3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. The p.Gly189Trp variant is observed in this individual in compound heterozygous state with a previously established Likely pathogenic variant (VCV000948224.5). In addition, the proband's phenotype matches to that of the disorder caused by pathogenic variants in CLN3. For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.81). A different missense change at the same codon (p.Gly189Arg) has been reported to be associated with CLN3 related disorder (ClinVar ID: VCV000056282 / PMID: 21990111). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;D;.;.;D;.;D;D;.;.;.;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;.;D;.;D;D;.;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	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;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.2	.;.;D;.;D;D;D;D;.;D;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;D;D;D;D;.;D;.;.;D
Sift4G	Pathogenic	0.0	.;.;.;D;.;D;D;D;.;D;.;.;.
Polyphen		1.0	.;D;D;.;.;.;.;D;.;D;.;.;.
Vest4		0.94, 0.94, 0.92, 0.87
MutPred		0.88		Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);.;.;.;Loss of disorder (P = 0.0165);.;Loss of disorder (P = 0.0165);.;.;.;
MVP		0.96
MPC		0.69
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.93
gMVP		0.92

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: rs386833731; hg19: chr16-28497780;