rs386833970

Variant names:

• chr13-76992238-T-TC
• rs386833970
• NM_006493.4:c.144dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006493.4(CLN5):​c.144dupC​(p.Ser49LeufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,028 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S49S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CLN5 NM_006493.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.220
• Publications: 2 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-76992238-T-TC is Pathogenic according to our data. Variant chr13-76992238-T-TC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 56532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.144dupC	p.Ser49LeufsTer13	frameshift	Exon 1 of 4	NP_006484.2	O75503
	CLN5	NM_001366624.2		c.144dupC	p.Ser49LeufsTer13	frameshift	Exon 1 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.144dupC	p.Ser49LeufsTer13	frameshift	Exon 1 of 4	ENSP00000366673.5	O75503
	CLN5	ENST00000636183.2	TSL:1	c.144dupC	p.Ser49LeufsTer13	frameshift	Exon 1 of 4	ENSP00000490181.2	O75503
	ENSG00000283208	ENST00000638147.2	TSL:5	c.144dupC	p.Ser49LeufsTer13	frameshift	Exon 1 of 5	ENSP00000490953.2	A0A1B0GWJ7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436028 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 713664

African (AFR) AF: 0.00 AC: 0 AN: 32972

American (AMR) AF: 0.0000234 AC: 1 AN: 42692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25724

East Asian (EAS) AF: 0.00 AC: 0 AN: 38996

South Asian (SAS) AF: 0.00 AC: 0 AN: 84372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4162

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104850

Other (OTH) AF: 0.00 AC: 0 AN: 59436

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Neuronal ceroid lipofuscinosis (2)
2	-	-	Neuronal ceroid lipofuscinosis 5 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.22
Mutation Taster		=27/173	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs386833970; hg19: chr13-77566373;