chr16-28477557-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001042432.2(CLN3):​c.1276C>G​(p.Leu426Val) 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 benign outcome for this variant. 13/21 in silico tools predict a benign 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

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.123
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.2280733).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CLN3NM_001042432.2 linkuse as main transcriptc.1276C>G p.Leu426Val missense_variant 16/16 ENST00000636147.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLN3ENST00000636147.2 linkuse as main transcriptc.1276C>G p.Leu426Val missense_variant 16/161 NM_001042432.2 P1Q13286-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 11, 2021In 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with CLN3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 426 of the CLN3 protein (p.Leu426Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Uncertain
0.060
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
5.6
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.60
D;D;.;.;T;.;.;T;D;T;.;T;.;.
Eigen
Benign
-0.64
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.46
N
LIST_S2
Benign
0.81
.;.;T;.;.;T;T;T;.;T;T;T;.;T
M_CAP
Uncertain
0.099
D
MetaRNN
Benign
0.23
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.075
D
MutationAssessor
Benign
1.3
L;L;.;.;.;.;.;.;L;.;.;.;.;.
MutationTaster
Benign
0.86
D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-1.1
.;N;.;.;N;N;N;N;N;.;N;.;.;N
REVEL
Benign
0.29
Sift
Benign
0.14
.;T;.;.;T;T;T;T;T;.;T;.;.;T
Sift4G
Benign
0.32
.;.;T;.;T;T;T;.;T;.;T;.;.;.
Polyphen
0.0040
B;B;.;.;B;.;.;.;B;B;B;B;.;B
Vest4
0.24, 0.25, 0.28, 0.27, 0.24, 0.33
MutPred
0.65
Gain of glycosylation at S423 (P = 0.0969);Gain of glycosylation at S423 (P = 0.0969);.;.;.;.;.;.;Gain of glycosylation at S423 (P = 0.0969);.;.;.;.;.;
MVP
0.75
MPC
0.16
ClinPred
0.11
T
GERP RS
-1.1
Varity_R
0.085
gMVP
0.48

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: rs1596619187; hg19: chr16-28488878; API