16-28477739-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001042432.2(CLN3):​c.1195G>A​(p.Glu399Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

CLN3
NM_001042432.2 missense, splice_region

Scores

6
10
3
Splicing: ADA: 0.9307
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.15
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CLN3NM_001042432.2 linkuse as main transcriptc.1195G>A p.Glu399Lys missense_variant, splice_region_variant 15/16 ENST00000636147.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLN3ENST00000636147.2 linkuse as main transcriptc.1195G>A p.Glu399Lys missense_variant, splice_region_variant 15/161 NM_001042432.2 P1Q13286-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.30
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.78
D;D;.;D;.;.;D;D;D;.;D;.;.
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.86
.;.;.;.;D;D;D;.;D;D;D;.;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Uncertain
2.3
M;M;.;.;.;.;.;M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-2.7
.;D;.;D;D;D;.;D;.;D;.;.;N
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0030
.;D;.;D;D;D;.;D;.;D;.;.;D
Sift4G
Benign
0.13
.;.;.;T;T;D;.;T;.;T;.;.;.
Polyphen
1.0
D;D;.;D;.;.;.;D;D;D;D;.;D
Vest4
0.49, 0.49, 0.48, 0.49, 0.49
MutPred
0.63
Gain of ubiquitination at E399 (P = 0.0131);Gain of ubiquitination at E399 (P = 0.0131);.;.;.;.;.;Gain of ubiquitination at E399 (P = 0.0131);.;.;.;.;.;
MVP
0.94
MPC
0.30
ClinPred
0.97
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.69
gMVP
0.66

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.93
dbscSNV1_RF
Pathogenic
0.76
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: rs386833701; hg19: chr16-28489060; COSMIC: COSV104658623; COSMIC: COSV104658623; API