rs77595156

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042432.2(CLN3):c.1211A>G(p.His404Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0549 in 1,613,844 control chromosomes in the GnomAD database, including 5,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H404N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.11 ( 1778 hom., cov: 33)

Exomes 𝑓: 0.049 ( 3616 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.04

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019387603).

BP6

Variant 16-28477622-T-C is Benign according to our data. Variant chr16-28477622-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28477622-T-C is described in Lovd as [Pathogenic]. Variant chr16-28477622-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN3	NM_001042432.2 link	c.1211A>G	p.His404Arg	missense_variant	Exon 16 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.1211A>G	p.His404Arg	missense_variant	Exon 16 of 16	1	NM_001042432.2	ENSP00000490105.1		Q13286-1
ENSG00000261832	ENST00000637378.1 link	c.228+4483A>G		intron_variant	Intron 4 of 9	5		ENSP00000490831.1		A0A1B0GW90

Frequencies

GnomAD3 genomes

AF:

0.113

AC:

17161

AN:

152020

Hom.:

1771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0631

Gnomad ASJ

AF:

0.0363

Gnomad EAS

AF:

0.123

Gnomad SAS

AF:

0.159

Gnomad FIN

AF:

0.0730

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0333

Gnomad OTH

AF:

0.0858

GnomAD3 exomes

AF:

0.0759

AC:

18997

AN:

250390

Hom.:

1403

AF XY:

0.0749

AC XY:

10149

AN XY:

135416

show subpopulations

Gnomad AFR exome

AF:

0.281

Gnomad AMR exome

AF:

0.0389

Gnomad ASJ exome

AF:

0.0364

Gnomad EAS exome

AF:

0.128

Gnomad SAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.0719

Gnomad NFE exome

AF:

0.0337

Gnomad OTH exome

AF:

0.0471

GnomAD4 exome

AF:

0.0488

AC:

71386

AN:

1461706

Hom.:

3616

Cov.:

AF XY:

0.0513

AC XY:

37282

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.283

Gnomad4 AMR exome

AF:

0.0404

Gnomad4 ASJ exome

AF:

0.0364

Gnomad4 EAS exome

AF:

0.0987

Gnomad4 SAS exome

AF:

0.155

Gnomad4 FIN exome

AF:

0.0655

Gnomad4 NFE exome

AF:

0.0311

Gnomad4 OTH exome

AF:

0.0586

GnomAD4 genome

AF:

0.113

AC:

17205

AN:

152138

Hom.:

1778

Cov.:

AF XY:

0.116

AC XY:

8625

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.276

Gnomad4 AMR

AF:

0.0629

Gnomad4 ASJ

AF:

0.0363

Gnomad4 EAS

AF:

0.123

Gnomad4 SAS

AF:

0.159

Gnomad4 FIN

AF:

0.0730

Gnomad4 NFE

AF:

0.0332

Gnomad4 OTH

AF:

0.0878

Alfa

AF:

0.0463

Hom.:

614

Bravo

AF:

0.115

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0254

AC:

ESP6500AA

AF:

0.269

AC:

1180

ESP6500EA

AF:

0.0316

AC:

272

ExAC

AF:

0.0807

AC:

9797

Asia WGS

AF:

0.132

AC:

456

AN:

3478

EpiCase

AF:

0.0318

EpiControl

AF:

0.0290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 28, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 3

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mar 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 22, 2016

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, Dominant/Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.77

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

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

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

MetaRNN

Benign

0.0019

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.3

MutationAssessor

Uncertain

2.0

M;M;.;.;.;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.9

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

REVEL

Uncertain

0.57

Sift

Benign

0.55

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

Sift4G

Benign

0.12

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

Polyphen

1.0

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

Vest4

0.41, 0.17, 0.19, 0.20, 0.12, 0.33

MPC

0.70

ClinPred

0.017

GERP RS

5.0

Varity_R

0.42

gMVP

0.54

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