chr16-28477548-G-A

Position:

• chr16-28477548-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001042432.2(CLN3):​c.1285C>T​(p.Pro429Ser) variant causes a missense change. 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: 33)
• Consequence: CLN3 NM_001042432.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.46

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN3	NM_001042432.2	c.1285C>T	p.Pro429Ser	missense_variant	16/16	ENST00000636147.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN3	ENST00000636147.2	c.1285C>T	p.Pro429Ser	missense_variant	16/16	1	NM_001042432.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 10, 2018

- -

Neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 23, 2022

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 429 of the CLN3 protein (p.Pro429Ser). 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: 585706). 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: "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. -

Neuronal ceroid lipofuscinosis 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D;D;.;.;D;.;.;D;D;D;.;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;.;D;.;.;D;D;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.3	.;D;.;.;D;D;D;.;D;.;D;.;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	.;D;.;.;D;D;D;.;D;.;D;.;.;D
Sift4G	Pathogenic	0.0	.;.;D;.;D;T;D;.;D;.;D;.;.;.
Polyphen		1.0	D;D;.;.;D;.;.;.;D;D;D;D;.;D
Vest4		0.57, 0.68, 0.65, 0.60, 0.68, 0.69
MutPred		0.76		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;.;.;.;.;.;Gain of helix (P = 0.0325);.;.;.;.;.;
MVP		0.96
MPC		0.64
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.80

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

Publications

LitVar

Other links and lift over

dbSNP: rs1433950864; hg19: chr16-28488869;