chr16-28487723-T-C

Position:

chr16-28487723-T-C

Variant summary

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

The ENST00000636147.2(CLN3):c.313A>G(p.Ile105Val) variant causes a missense change. The variant allele was found at a frequency of 0.00314 in 1,613,650 control chromosomes in the GnomAD database, including 148 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. I105F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0035 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 135 hom. )

Consequence

CLN3
ENST00000636147.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.17

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:

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=0.012943447).

BP6

Variant 16-28487723-T-C is Benign according to our data. Variant chr16-28487723-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-28487723-T-C is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN3	NM_001042432.2 linkuse as main transcript	c.313A>G	p.Ile105Val	missense_variant	6/16	ENST00000636147.2	NP_001035897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN3	ENST00000636147.2 linkuse as main transcript	c.313A>G	p.Ile105Val	missense_variant	6/16	1	NM_001042432.2	ENSP00000490105	P1	Q13286-1

Frequencies

GnomAD3 genomes

AF:

0.00353

AC:

537

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0249

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00937

AC:

2341

AN:

249936

Hom.:

AF XY:

0.00731

AC XY:

988

AN XY:

135226

show subpopulations

Gnomad AFR exome

AF:

0.00285

Gnomad AMR exome

AF:

0.0499

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0282

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00309

AC:

4523

AN:

1461474

Hom.:

135

Cov.:

AF XY:

0.00279

AC XY:

2028

AN XY:

727004

show subpopulations

Gnomad4 AFR exome

AF:

0.00143

Gnomad4 AMR exome

AF:

0.0463

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0539

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000720

Gnomad4 OTH exome

AF:

0.00270

GnomAD4 genome

AF:

0.00354

AC:

539

AN:

152176

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

279

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00193

Gnomad4 AMR

AF:

0.0195

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0252

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00205

Hom.:

Bravo

AF:

0.00600

ESP6500AA

AF:

0.00273

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00799

AC:

970

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 10, 2020	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2016

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. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuronal ceroid lipofuscinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Neuronal ceroid lipofuscinosis 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

.;D;D;.;.;T;.;D;T;.;T;.;.;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;.;.;D;.;.;D;.;D;D;D;.;T;T

MetaRNN

Benign

0.013

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

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.8

.;L;L;.;.;.;.;L;.;L;.;.;L;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.75

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

REVEL

Pathogenic

0.70

Sift

Benign

0.21

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

Sift4G

Benign

0.13

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

Polyphen

1.0, 0.99, 1.0

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

Vest4

0.51, 0.50, 0.48, 0.47, 0.59

MVP

0.83

MPC

0.58

ClinPred

0.024

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.42

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

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