rs386833708

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong

The NM_001042432.2(CLN3):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 start_lost

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 2.17

Variant links:

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 links:

ENSG00000261832 (HGNC:):

ENSG00000261832 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 55 codons. Genomic position: 28489349. Lost 0.124 part of the original CDS.

PS1

Another start lost variant in NM_001042432.2 (CLN3) was described as [Pathogenic] in Lovd

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-28491759-T-C is Pathogenic according to our data. Variant chr16-28491759-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 16	ENST00000636147.2	NP_001035897.1	Q13286-1A0A024QZB8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 link	c.1A>G	p.Met1?	start_lost	Exon 2 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250966

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135700

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis

Pathogenic:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CLN3 mRNA. The next in-frame methionine is located at codon 55. This variant is present in population databases (rs386833708, gnomAD 0.006%). Disruption of the initiator codon has been observed in individuals with Neuronal ceroid lipofuscinosis and/or retinitis pigmentosa (PMID: 32154056; internal data). ClinVar contains an entry for this variant (Variation ID: 550268). For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis 3

Pathogenic:1

Dec 27, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CLN3-related disorder

Pathogenic:1

Apr 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CLN3 c.1A>G variant is predicted to disrupt the translation initiation site (Start loss). This variant has not been reported in the literature, however other variant c.1A>C disrupting initiation codon has been reported in compound heterozygous state in three individuals with attenuated form of CLN3 disease (Kuper et al 2020. PubMed ID: 32154056). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-28503080-T-C). In summary, we interpret this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.50

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;T;T;.;.;.;.;T;.;.;.;T;T;T;T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.90

D;.;.;D;.;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

PROVEAN

Benign

-0.56

.;.;N;.;N;N;N;N;N;N;.;N;N;N;N;N

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

.;.;D;.;D;D;D;D;D;D;.;D;D;D;D;D

Sift4G

Pathogenic

0.0

.;.;.;D;D;D;D;D;D;D;.;D;.;.;.;D

Polyphen

0.86, 0.92, 0.98, 0.63

.;P;P;.;.;.;.;P;P;D;.;P;.;.;.;.

Vest4

0.70, 0.81, 0.81, 0.76, 0.82, 0.78, 0.61

MutPred

1.0

Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);Loss of MoRF binding (P = 0.102);

MVP

0.93

ClinPred

0.99

GERP RS

4.8

Varity_R

0.84

gMVP

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over