rs373911322

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4BP6_Very_StrongBP7BS1BS2

The NM_001042432.2(CLN3):c.240G>A(p.Thr80Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,614,102 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 7 hom. )

Consequence

CLN3
NM_001042432.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -2.12

Publications

2 publications found

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 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

CLN3 links:

ENSG00000261832 (HGNC:):

ENSG00000261832 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.288).

BP6

Variant 16-28488645-C-T is Benign according to our data. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28488645-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 197712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000256 (39/152250) while in subpopulation SAS AF = 0.00725 (35/4830). AF 95% confidence interval is 0.00536. There are 1 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.240G>A	p.Thr80Thr	synonymous_variant	Exon 5 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.240G>A	p.Thr80Thr	synonymous_variant	Exon 5 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00765

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000962

AC:

242

AN:

251490

AF XY:

0.00127

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000490

AC:

716

AN:

1461852

Hom.:

Cov.:

AF XY:

0.000650

AC XY:

473

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.00772

AC:

666

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111986

Other (OTH)

AF:

0.000546

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

134

179

224

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000256

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00725

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000793

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 05, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 13, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 01, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neuronal ceroid lipofuscinosis

Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CLN3-related disorder

Benign:1

Jul 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neuronal ceroid lipofuscinosis 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

0.43

(source)

DANN

Benign

0.96

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over