rs139842473

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 12P and 1B. PP3_StrongPP5_Very_StrongBS1_Supporting

The NM_001042432.2(CLN3):c.1213C>T(p.Arg405Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,613,866 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R405Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CLN3
NM_001042432.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 3.48

Publications

18 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: Pathogenic. The variant received 11 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 16-28477620-G-A is Pathogenic according to our data. Variant chr16-28477620-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 418137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00018 (263/1461714) while in subpopulation NFE AF = 0.000222 (247/1112008). AF 95% confidence interval is 0.000199. There are 0 homozygotes in GnomAdExome4. There are 132 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1213C>T	p.Arg405Trp	missense	Exon 16 of 16	NP_001035897.1	Q13286-1
CLN3	NM_000086.2		c.1213C>T	p.Arg405Trp	missense	Exon 15 of 15	NP_000077.1	Q13286-1
CLN3	NM_001286104.2		c.1141C>T	p.Arg381Trp	missense	Exon 15 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.1213C>T	p.Arg405Trp	missense	Exon 16 of 16	ENSP00000490105.1	Q13286-1
CLN3	ENST00000359984.12	TSL:1	c.1213C>T	p.Arg405Trp	missense	Exon 15 of 15	ENSP00000353073.9	Q13286-1
CLN3	ENST00000565316.6	TSL:1	c.1162C>T	p.Arg388Trp	missense	Exon 14 of 14	ENSP00000456117.1	Q13286-3

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000719

AC:

AN:

250418

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000974

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

263

AN:

1461714

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000222

AC:

247

AN:

1112008

Other (OTH)

AF:

0.000116

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000723

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000158

Hom.:

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis 3 (6)

Retinitis pigmentosa (5)

not provided (3)

Neuronal ceroid lipofuscinosis (2)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.5

PhyloP100

3.5

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.60

MVP

0.96

MPC

0.64

ClinPred

0.97

GERP RS

4.1

Varity_R

0.89

gMVP

0.88

Mutation Taster

=0/100

disease causing (ClinVar)

(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