rs756848924

chr16-28482621-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000565316.6(CLN3):c.842G>A(p.Arg281Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R281W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CLN3 ENST00000565316.6 missense
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: 0.893

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 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	UniProt
CLN3	NM_001042432.2	c.837+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.837+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.0000636 AC: 16 AN: 251416 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461860 Hom.: 0 Cov.: 33 AF XY: 0.0000440 AC XY: 32 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

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

Alfa AF: 0.0000478 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The splice region c.837+5G>A variant in CLN3 gene has been reported previously in compound heterozygous state in an individual affected with Ceroid lipofuscinosis (Ku CA, et. al.,2017). The variant is reported with an allele frequency of 0.006% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain significance/ Likely pathogenic. SpliceAI predicts a donor loss of 0.64 for this variant. Loss of function variants have been previously reported to be disease causing. Functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -

Retinitis pigmentosa Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.837+5G>A intronic alteration consists of a G to A substitution 5 nucleotides after exon 11 (coding exon 10) of the CLN3 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2022

This sequence change falls in intron 11 of the CLN3 gene. It does not directly change the encoded amino acid sequence of the CLN3 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756848924, gnomAD 0.03%). This variant has been observed in individual(s) with isolated retinal degeneration (PMID: 28542676). ClinVar contains an entry for this variant (Variation ID: 318720). 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
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	12
Dann	Uncertain	0.99
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.46	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N
Polyphen		0.81	.;P
Vest4		0.21
MutPred		0.60		Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);
MVP		0.80
ClinPred		0.022	T
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.64		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756848924; hg19: chr16-28493942; COSMIC: COSV61105486; COSMIC: COSV61105486;