rs886285802

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_017882.3(CLN6):c.13C>T(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,467,030 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 3.49

Variant links:

Genes affected

CLN6 (HGNC:2077): (CLN6 transmembrane ER protein) This gene is one of eight which have been associated with neuronal ceroid lipofuscinoses (NCL). Also referred to as Batten disease, NCL comprises a class of autosomal recessive, neurodegenerative disorders affecting children. The genes responsible likely encode proteins involved in the degradation of post-translationally modified proteins in lysosomes. The primary defect in NCL disorders is thought to be associated with lysosomal storage function. [provided by RefSeq, Oct 2008]

CLN6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

PP5

Variant 15-68229572-G-A is Pathogenic according to our data. Variant chr15-68229572-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457969.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN6	NM_017882.3 linkuse as main transcript	c.13C>T	p.Arg5Trp	missense_variant	1/7	ENST00000249806.11
CLN6	NM_001411068.1 linkuse as main transcript	c.180-10922C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11 linkuse as main transcript	c.13C>T	p.Arg5Trp	missense_variant	1/7	1	NM_017882.3	P1	Q9NWW5-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151918

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000248

AC:

AN:

80612

Hom.:

AF XY:

0.0000217

AC XY:

AN XY:

46014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000345

Gnomad OTH exome

AF:

0.000423

GnomAD4 exome

AF:

0.0000738

AC:

AN:

1315112

Hom.:

Cov.:

AF XY:

0.0000740

AC XY:

AN XY:

648626

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000908

Gnomad4 OTH exome

AF:

0.0000368

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151918

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74220

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33144682, 28831385, 21990111, 33024953) -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 07, 2017	- -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the CLN6 protein (p.Arg5Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111, 28831385, 33024953). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 457969). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLN6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 31, 2023

Variant summary: CLN6 c.13C>T (p.Arg5Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 80612 control chromosomes (gnomAD). c.13C>T has been reported in the literature in the compound heterozygous state together with a VUS in three siblings with clinical features of Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Vairo_2017), in trans with a pathogenic variant an individual who underwent whole genome sequencing, confirming a diagnosis of Kufs disease/Neuronal Ceroid-Lipofuscinosis (Talbot_2020), and in the heterozygous state in at least one other affected individual (Kousi_2012). These data suggest the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21990111, 33024953, 28831385). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Ceroid lipofuscinosis, neuronal, 6A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Feb 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

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

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

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

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.92

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

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

1.4

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

MutationTaster

Benign

1.0

D;D;N;N;N;N

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.7

D;D;N;D;.;.;D;.

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0080

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.47

MutPred

0.75

Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);Loss of disorder (P = 0.0134);

MVP

0.98

MPC

0.090

ClinPred

0.97

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.24

gMVP

0.46

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