chr16-28477548-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_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

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.46
Variant links:
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]

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ACMG classification

Classification made for transcript

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
CLN3NM_001042432.2 linkuse as main transcriptc.1285C>T p.Pro429Ser missense_variant 16/16 ENST00000636147.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLN3ENST00000636147.2 linkuse as main transcriptc.1285C>T p.Pro429Ser missense_variant 16/161 NM_001042432.2 P1Q13286-1

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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsApr 10, 2018- -
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 23, 2022This 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 submitterclinical testingGenome-Nilou LabSep 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1433950864; hg19: chr16-28488869; API