NM_001042432.2:c.482C>T

Variant names:

• chr16-28486629-G-A
• rs386833724
• NM_001042432.2:c.482C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001042432.2(CLN3):​c.482C>T​(p.Ser161Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,192 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S161S) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001042432.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.482C>T	p.Ser161Leu	missense_variant	Exon 8 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.482C>T	p.Ser161Leu	missense_variant	Exon 8 of 16	1	NM_001042432.2	ENSP00000490105.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1

Jun 25, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has been observed in individual(s) with clinical features of retinitis pigmentosa (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with leucine at codon 161 of the CLN3 protein (p.Ser161Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;D;.;.;D;.;D;D;.;D;.;.;.;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D;.;.;D;.;.;D;.;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.8	.;H;H;.;.;.;.;H;.;H;.;.;H;.;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	.;.;D;.;.;D;D;D;.;D;.;.;D;.;D;.
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	.;.;D;.;.;D;D;D;.;D;.;.;D;.;D;.
Sift4G	Uncertain	0.0040	.;.;.;D;.;D;D;D;.;D;.;.;.;.;.;.
Polyphen		1.0	.;D;D;.;.;.;.;D;.;D;D;.;D;.;.;.
Vest4		0.68, 0.68, 0.67, 0.68, 0.66
MutPred		0.86		Loss of catalytic residue at S161 (P = 0.0825);Loss of catalytic residue at S161 (P = 0.0825);Loss of catalytic residue at S161 (P = 0.0825);Loss of catalytic residue at S161 (P = 0.0825);.;.;.;Loss of catalytic residue at S161 (P = 0.0825);.;Loss of catalytic residue at S161 (P = 0.0825);.;.;Loss of catalytic residue at S161 (P = 0.0825);.;.;.;
MVP		0.97
MPC		0.60
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.88

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

Other links and lift over

dbSNP: rs386833724; hg19: chr16-28497950;