16-28486577-C-T

Variant names:

• chr16-28486577-C-T
• rs386833728
• NM_001042432.2:c.533+1G>A

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.533+1G>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLN3 NM_001042432.2 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.23
• Publications: 1 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: Orphanet, Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ENSG00000261832 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4, offset of 43, new splice context is: atgGTcagc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-28486577-C-T is Pathogenic according to our data. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-28486577-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 56278.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2	c.533+1G>A		splice_donor_variant, intron_variant	Intron 8 of 15	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2	c.533+1G>A		splice_donor_variant, intron_variant	Intron 8 of 15	1	NM_001042432.2	ENSP00000490105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458376 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725188

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110514

Other (OTH) AF: 0.00 AC: 0 AN: 60262

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Retinal dystrophy Pathogenic:1

Jun 15, 2019

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 3 Pathogenic:1

-

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.2
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs386833728; hg19: chr16-28497898;