16-28487536-CG-CGG

Variant names:

• chr16-28487536-C-CG
• rs386833717
• NM_001042432.2:c.379dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001042432.2(CLN3):​c.379dupC​(p.Arg127ProfsTer33) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R127R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLN3 NM_001042432.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.15
• Publications: 0 publications found

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]

CLN3 Gene-Disease associations (from GenCC):

• inherited retinal dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 3

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

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 16-28487536-C-CG is Pathogenic according to our data. Variant chr16-28487536-C-CG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2680813.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042432.2. 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
	CLN3	NM_001042432.2	MANE Select	c.379dupC	p.Arg127ProfsTer33	frameshift	Exon 7 of 16	NP_001035897.1	Q13286-1
	CLN3	NM_000086.2		c.379dupC	p.Arg127ProfsTer33	frameshift	Exon 6 of 15	NP_000077.1	Q13286-1
	CLN3	NM_001286104.2		c.307dupC	p.Arg103ProfsTer33	frameshift	Exon 6 of 15	NP_001273033.1	Q13286-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN3	ENST00000636147.2	TSL:1 MANE Select	c.379dupC	p.Arg127ProfsTer33	frameshift	Exon 7 of 16	ENSP00000490105.1	Q13286-1
	CLN3	ENST00000359984.12	TSL:1	c.379dupC	p.Arg127ProfsTer33	frameshift	Exon 6 of 15	ENSP00000353073.9	Q13286-1
	CLN3	ENST00000565316.6	TSL:1	c.379dupC	p.Arg127ProfsTer33	frameshift	Exon 6 of 14	ENSP00000456117.1	Q13286-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neuronal ceroid lipofuscinosis 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

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: rs386833717; hg19: chr16-28498857; COSMIC: COSV61105368; COSMIC: COSV61105368;