13-76992003-C-T

Variant names:

• chr13-76992003-C-T
• rs773979248
• ENST00000636183.2:c.-96C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The ENST00000636183.2(CLN5):​c.-96C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000362 in 1,602,384 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (1 hom.)
• Consequence: CLN5 ENST00000636183.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -1.14
• Publications: 1 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]

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

ENSG00000283208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.-96C>T		upstream_gene	N/A	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.-96C>T		upstream_gene	N/A	NP_001353553.1	A0A1B0GTR6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN5	ENST00000636183.2	TSL:1	c.-96C>T		5_prime_UTR	Exon 1 of 4	ENSP00000490181.2	O75503
	CLN5	ENST00000377453.9	TSL:1 MANE Select	c.-96C>T		upstream_gene	N/A	ENSP00000366673.5	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.-96C>T		upstream_gene	N/A	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000791 AC: 17 AN: 214828 AF XY: 0.000109

Gnomad AFR exome AF: 0.000165

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000108

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000379 AC: 55 AN: 1450204 Hom.: 1 Cov.: 34 AF XY: 0.0000499 AC XY: 36 AN XY: 721034

African (AFR) AF: 0.0000901 AC: 3 AN: 33292

American (AMR) AF: 0.00 AC: 0 AN: 43888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.000446 AC: 38 AN: 85116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5476

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1108878

Other (OTH) AF: 0.0000167 AC: 1 AN: 59916

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000305 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000598 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Neuronal ceroid lipofuscinosis 5 (2)
-	1	-	Neuronal ceroid lipofuscinosis (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Benign	-0.20
CADD	Benign	0.67
DANN	Benign	0.86
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.050	N
PhyloP100		-1.1
GERP RS		0.68
PromoterAI		-0.18	Neutral
Mutation Taster		=131/69	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs773979248; hg19: chr13-77566138;