13-77000882-G-C

Variant names:

• chr13-77000882-G-C
• NM_006493.4:c.990G>C
• CLN5 p.Trp330Cys

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1_Moderate PM1 PM2 PP3_Moderate

The NM_006493.4(CLN5):​c.990G>C​(p.Trp330Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN5 NM_006493.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86
• Publications: 0 publications found

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]

ENSG00000283208 (HGNC:):

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]

FBXL3 Gene-Disease associations (from GenCC):

• intellectual disability, short stature, facial anomalies, and joint dislocations

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_006493.4 (CLN5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006493.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006493.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	NM_006493.4	MANE Select	c.990G>C	p.Trp330Cys	missense	Exon 4 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.*439G>C		3_prime_UTR	Exon 5 of 5	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.990G>C	p.Trp330Cys	missense	Exon 4 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.990G>C	p.Trp330Cys	missense	Exon 4 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.565+4755G>C		intron	N/A	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.9
PrimateAI	Uncertain	0.76	T
REVEL	Pathogenic	0.95
Varity_R		0.90
Mutation Taster		=13/87	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr13-77575017;