Genetic Variant CLN5:c.-47C>T (chr13-76992052-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000636183.2(CLN5):c.-47C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CLN5
ENST00000636183.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.306

Publications

0 publications found

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]

CLN5 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

CLN5 links:

ENSG00000283208 (HGNC:):

ENSG00000283208 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10929692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN5	NM_006493.4 link	c.-47C>T		upstream_gene_variant		ENST00000377453.9	NP_006484.2	O75503A0A024R644
CLN5	NM_001366624.2 link	c.-47C>T		upstream_gene_variant			NP_001353553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN5	ENST00000377453.9 link	c.-47C>T		upstream_gene_variant		1	NM_006493.4	ENSP00000366673.5		O75503
ENSG00000283208	ENST00000638147.2 link	c.-47C>T		upstream_gene_variant		5		ENSP00000490953.2		A0A1B0GWJ7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000436

AC:

AN:

229406

AF XY:

0.00000786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000571

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33408

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86044

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111068

Other (OTH)

AF:

0.00

AC:

AN:

60130

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.56

CADD

Benign

4.9

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.073

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.43

M_CAP

Benign

0.0085

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

PhyloP100

-0.31

PrimateAI

Uncertain

0.64

MutPred

0.23

Loss of glycosylation at P34 (P = 0.01);

ClinPred

0.64

GERP RS

-5.7

PromoterAI

0.012

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over