chr13-76995065-G-A

Variant summary

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

The NM_006493.4(CLN5):​c.176G>A​(p.Arg59His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,254 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CLN5
NM_006493.4 missense, splice_region

Scores

6
8
2

Clinical Significance

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

Conservation

PhyloP100: 8.14
Variant links:
Genes affected
CLN5 (HGNC:2076): (CLN5 intracellular trafficking protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function.[provided by RefSeq, Oct 2008]
FBXL3 (HGNC:13599): (F-box and leucine rich repeat protein 3) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains several tandem leucine-rich repeats and is localized in the nucleus. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons MANE UniProt
CLN5NM_006493.4 linkuse as main transcriptc.176G>A p.Arg59His missense_variant, splice_region_variant 2/4 ENST00000377453.9
CLN5NM_001366624.2 linkuse as main transcriptc.176G>A p.Arg59His missense_variant, splice_region_variant 2/5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CLN5ENST00000377453.9 linkuse as main transcriptc.176G>A p.Arg59His missense_variant, splice_region_variant 2/41 NM_006493.4 P1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152152
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
250850
Hom.:
0
AF XY:
0.0000443
AC XY:
6
AN XY:
135556
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000240
AC:
35
AN:
1461102
Hom.:
0
Cov.:
31
AF XY:
0.0000330
AC XY:
24
AN XY:
726814
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152152
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000227
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 30, 2022The c.323G>A (p.R108H) alteration is located in exon 2 (coding exon 2) of the CLN5 gene. This alteration results from a G to A substitution at nucleotide position 323, causing the arginine (R) at amino acid position 108 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Neuronal ceroid lipofuscinosis 5 Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Neuronal ceroid lipofuscinosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 12, 2022This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 108 of the CLN5 protein (p.Arg108His). This variant is present in population databases (rs753197537, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 643941). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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
Uncertain
0.54
BayesDel_addAF
Uncertain
0.027
T
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.30
T;T;D;T;T;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;.;D;.;.;.
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.73
D;D;D;D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Uncertain
2.4
.;.;M;.;.;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.79
T
REVEL
Pathogenic
0.66
Polyphen
1.0
.;.;D;.;.;.
MutPred
0.46
.;.;Loss of methylation at R59 (P = 0.024);.;.;.;
MVP
0.99
MPC
0.81
ClinPred
0.80
D
GERP RS
5.8
Varity_R
0.19

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: rs753197537; hg19: chr13-77569200; COSMIC: COSV66284924; COSMIC: COSV66284924; API