13-76992000-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The ENST00000636183.2(CLN5):c.-99G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000465 in 1,601,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

CLN5
ENST00000636183.2 5_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: -2.40

Publications

2 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet, G2P, Ambry Genetics, Genomics England PanelApp

CLN5 links:

ENSG00000283208 (HGNC:):

ENSG00000283208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044178665).

BP6

Variant 13-76992000-G-C is Benign according to our data. Variant chr13-76992000-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205123.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00197 (300/152318) while in subpopulation AFR AF = 0.00645 (268/41576). AF 95% confidence interval is 0.00581. There are 1 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000636183.2. 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.-99G>C		upstream_gene	N/A	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.-99G>C		upstream_gene	N/A	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLN5	ENST00000636183.2	TSL:1	c.-99G>C	5_prime_UTR	Exon 1 of 4	ENSP00000490181.2	O75503
CLN5	ENST00000377453.9	TSL:1 MANE Select	c.-99G>C	upstream_gene	N/A	ENSP00000366673.5	O75503
ENSG00000283208	ENST00000638147.2	TSL:5	c.-99G>C	upstream_gene	N/A	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes

AF:

0.00196

AC:

299

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000551

AC:

118

AN:

214040

AF XY:

0.000462

show subpopulations

Gnomad AFR exome

AF:

0.00507

Gnomad AMR exome

AF:

0.000576

Gnomad ASJ exome

AF:

0.00282

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000866

Gnomad OTH exome

AF:

0.000557

GnomAD4 exome

AF:

0.000307

AC:

445

AN:

1449574

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

215

AN XY:

720728

show subpopulations

African (AFR)

AF:

0.00748

AC:

249

AN:

33278

American (AMR)

AF:

0.000547

AC:

AN:

43856

Ashkenazi Jewish (ASJ)

AF:

0.00275

AC:

AN:

25850

East Asian (EAS)

AF:

0.00

AC:

AN:

39314

South Asian (SAS)

AF:

0.0000353

AC:

AN:

85084

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48138

Middle Eastern (MID)

AF:

0.00183

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.0000307

AC:

AN:

1108694

Other (OTH)

AF:

0.000902

AC:

AN:

59888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

114

142

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

AF:

0.00197

AC:

300

AN:

152318

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

137

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00645

AC:

268

AN:

41576

American (AMR)

AF:

0.000784

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68028

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000877

Hom.:

Bravo

AF:

0.00201

ESP6500AA

AF:

0.00285

AC:

ESP6500EA

AF:

0.000130

AC:

ExAC

AF:

0.000504

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Neuronal ceroid lipofuscinosis (2)

Neuronal ceroid lipofuscinosis 5 (2)

not specified (2)

Inborn genetic diseases (1)

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.60

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.068

Eigen

Benign

-0.75

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.30

M_CAP

Benign

0.0026

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.98

PhyloP100

-2.4

PrimateAI

Uncertain

0.59

MutPred

0.35

Loss of loop (P = 0.0112)

ClinPred

0.018

GERP RS

-1.9

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over