16-28487516-A-G

Position:

• chr16-28487516-A-G

Variant summary

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

The NM_001042432.2(CLN3):​c.400T>C​(p.Cys134Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 1.45

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.400T>C	p.Cys134Arg	missense_variant	7/16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.400T>C	p.Cys134Arg	missense_variant	7/16	1	NM_001042432.2	ENSP00000490105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

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

Dec 11, 2019

This sequence change replaces cysteine with arginine at codon 134 of the CLN3 protein (p.Cys134Arg). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with juvenile neuronal ceroid lipofuscinoses (PMID:21990111). ClinVar contains an entry for this variant (Variation ID: 56268). 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"). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.93	.;D;D;.;.;D;.;D;D;.;D;.;.;.;D;D
Eigen	Benign	-0.062
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.087	N
LIST_S2	Uncertain	0.89	D;.;.;D;.;.;D;.;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.7	.;M;M;.;.;.;.;M;.;M;.;.;M;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.3	.;.;D;.;.;D;D;D;.;D;.;.;D;.;D;.
REVEL	Uncertain	0.43
Sift	Benign	0.060	.;.;T;.;.;T;T;T;.;T;.;.;D;.;D;.
Sift4G	Benign	0.083	.;.;.;T;.;D;D;D;.;D;.;.;T;.;.;.
Polyphen		0.33, 0.66, 0.92, 0.81	.;B;B;.;.;.;.;B;.;P;P;.;P;.;.;.
Vest4		0.55, 0.55, 0.50, 0.55, 0.51
MutPred		0.89		Gain of methylation at C134 (P = 0.0037);Gain of methylation at C134 (P = 0.0037);Gain of methylation at C134 (P = 0.0037);Gain of methylation at C134 (P = 0.0037);.;.;.;Gain of methylation at C134 (P = 0.0037);.;Gain of methylation at C134 (P = 0.0037);.;.;Gain of methylation at C134 (P = 0.0037);.;.;.;
MVP		0.93
MPC		0.56
ClinPred		0.96	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs386833719; hg19: chr16-28498837;