16-28477560-GC-G

Position:

• chr16-28477560-GC-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001042432.2(CLN3):​c.1272delG​(p.Leu425fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLN3 NM_001042432.2 frameshift
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.833

Genes affected

CLN3 (HGNC:2074): (CLN3 lysosomal/endosomal transmembrane protein, battenin) This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

ENSG00000261832 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0342 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-28477560-GC-G is Pathogenic according to our data. Variant chr16-28477560-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 56256.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-28477560-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.1272delG	p.Leu425fs	frameshift_variant	16/16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.1272delG	p.Leu425fs	frameshift_variant	16/16	1	NM_001042432.2	ENSP00000490105.1
ENSG00000261832	ENST00000637378.1	c.228+4544delG		intron_variant		5		ENSP00000490831.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuronal ceroid lipofuscinosis 3 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

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Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs386833707; hg19: chr16-28488881;