rs386833699

chr16-28482105-C-Achr16-28482105-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001042432.2(CLN3):c.1056G>T(p.Gln352His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CLN3 NM_001042432.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.66

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 8 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.
• PP5: Variant 16-28482105-C-A is Pathogenic according to our data. Variant chr16-28482105-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 660322.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2	c.1056G>T	p.Gln352His	missense_variant, splice_region_variant	14/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.1056G>T	p.Gln352His	missense_variant, splice_region_variant	14/16	1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 02, 2019

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 352 of the CLN3 protein (p.Gln352His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 14 of the CLN3 coding sequence, which is part of the consensus splice site for this exon. This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Batten disease (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. It has also been reported in an unrelated affected individual in combination with a pathogenic CLN3 variant (PMID: 15818814). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T;.;.;.;.;D;D;D;.;D;D;D;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.50	T
Polyphen		1.0, 1.0	.;.;D;D;.;D;.;.;.;D;D;D;D;.;D;.
Vest4		0.90, 0.88, 0.83, 0.91
MutPred		0.92		.;.;Loss of MoRF binding (P = 0.1253);Loss of MoRF binding (P = 0.1253);.;.;.;.;.;Loss of MoRF binding (P = 0.1253);.;.;.;.;.;.;
MVP		0.96
MPC		0.62
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs386833699; hg19: chr16-28493426;