16-28487723-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001042432.2(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
NM_001042432.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.17

Publications

10 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: Ambry Genetics, Genomics England PanelApp, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

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 -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 Benign/Likely_benign. ClinVar VariationId is 128777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042432.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLN3	NM_001042432.2	MANE Select	c.313A>G	p.Ile105Val	missense	Exon 6 of 16	NP_001035897.1	Q13286-1
CLN3	NM_000086.2		c.313A>G	p.Ile105Val	missense	Exon 5 of 15	NP_000077.1	Q13286-1
CLN3	NM_001286104.2		c.241A>G	p.Ile81Val	missense	Exon 5 of 15	NP_001273033.1	Q13286-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLN3	ENST00000636147.2	TSL:1 MANE Select	c.313A>G	p.Ile105Val	missense	Exon 6 of 16	ENSP00000490105.1	Q13286-1
CLN3	ENST00000359984.12	TSL:1	c.313A>G	p.Ile105Val	missense	Exon 5 of 15	ENSP00000353073.9	Q13286-1
CLN3	ENST00000565316.6	TSL:1	c.313A>G	p.Ile105Val	missense	Exon 5 of 14	ENSP00000456117.1	Q13286-3

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

GnomAD2 exomes

AF:

0.00937

AC:

2341

AN:

249936

AF XY:

0.00731

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 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

African (AFR)

AF:

0.00143

AC:

AN:

33464

American (AMR)

AF:

0.0463

AC:

2070

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0539

AC:

2141

AN:

39688

South Asian (SAS)

AF:

0.000232

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.0000720

AC:

AN:

1111840

Other (OTH)

AF:

0.00270

AC:

163

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

278

556

834

1112

1390

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00354

AC:

539

AN:

152176

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

279

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

41536

American (AMR)

AF:

0.0195

AC:

297

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0252

AC:

130

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00278

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Inborn genetic diseases (1)

Neuronal ceroid lipofuscinosis (1)

Neuronal ceroid lipofuscinosis 3 (1)

Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.38

MutationAssessor

Benign

1.8

PhyloP100

6.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.75

REVEL

Pathogenic

0.70

Sift

Benign

0.21

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.51

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

Mutation Taster

=87/13

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over