16-28489306-G-C

Variant names:

• chr16-28489306-G-C
• rs769840061
• NM_001042432.2:c.206C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001286105.2(CLN3):​c.-15C>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000116 in 1,460,748 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CLN3 NM_001286105.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.07

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]

ENSG00000261832 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.206C>G	p.Ser69Trp	missense_variant	Exon 4 of 16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.206C>G	p.Ser69Trp	missense_variant	Exon 4 of 16	1	NM_001042432.2	ENSP00000490105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460748 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726550

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Uncertain:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Neuronal ceroid lipofuscinosis Uncertain:1

Feb 03, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 69 of the CLN3 protein (p.Ser69Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CLN3-related conditions. ClinVar contains an entry for this variant (Variation ID: 884834). 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 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	Benign	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	.;D;D;.;.;D;.;.;T;D;D;.;D;.;.;D;D;D;D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;.;.;D;.;.;D;D;D;.;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.2	.;M;M;.;M;.;M;M;.;M;.;M;.;.;M;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	.;.;N;.;N;N;D;D;.;N;.;D;.;.;D;D;.;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0090	.;.;D;.;D;D;D;D;.;D;.;D;.;.;D;D;.;D;D
Sift4G	Uncertain	0.018	.;.;.;D;D;D;D;D;.;D;.;D;.;.;D;D;.;.;D
Polyphen		0.99, 0.99, 0.99	.;D;D;.;.;.;.;.;.;D;.;D;D;.;D;D;.;.;.
Vest4		0.43, 0.42, 0.46, 0.49, 0.45, 0.45
MutPred		0.46		Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);.;Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);.;Loss of disorder (P = 0.0081);.;Loss of disorder (P = 0.0081);.;.;Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);.;Loss of disorder (P = 0.0081);
MVP		0.95
MPC		0.70
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.070
gMVP		0.42

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: rs769840061; hg19: chr16-28500627;