rs747229909

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_017882.3(CLN6):c.445C>T(p.Arg149Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,806 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).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 2.69

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:

ENSG00000260007 (HGNC:):

ENSG00000260007 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 15-68211716-G-A is Pathogenic according to our data. Variant chr15-68211716-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457972.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr15-68211716-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3 linkuse as main transcript	c.445C>T	p.Arg149Cys	missense_variant	4/7	ENST00000249806.11	NP_060352.1	Q9NWW5-1A0A024R601
CLN6	NM_001411068.1 linkuse as main transcript	c.541C>T	p.Arg181Cys	missense_variant	4/7		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 linkuse as main transcript	c.445C>T	p.Arg149Cys	missense_variant	4/7	1	NM_017882.3	ENSP00000249806.5		Q9NWW5-1
ENSG00000260007	ENST00000562767.2 linkuse as main transcript	c.84-14088C>T		intron_variant		3		ENSP00000456336.1		H3BRN7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251224

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 02, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 149 of the CLN6 protein (p.Arg149Cys). This variant is present in population databases (rs747229909, gnomAD 0.04%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111, 31741823). ClinVar contains an entry for this variant (Variation ID: 457972). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLN6 function (PMID: 32171521). This variant disrupts the p.Arg149 amino acid residue in CLN6. Other variant(s) that disrupt this residue have been observed in individuals with CLN6-related conditions (PMID: 21549341, 30561534), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2021	Variant summary: CLN6 c.445C>T (p.Arg149Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251224 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CLN6 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.445C>T has been reported in the literature as a non-informative genotype (second allele not specified) (example, Kousi_2012, Sleat_2016) and as a homozygous genotype in at-least three individuals (example Jiliani_2019) affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping but not all evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;.;T;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.84

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.2

M;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.9

D;D;.;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0070

D;D;.;D

Sift4G

Uncertain

0.0040

D;D;.;D

Polyphen

1.0

D;.;.;.

Vest4

0.91

MutPred

0.88

.;Loss of disorder (P = 0.0331);.;.;

MVP

0.94

MPC

1.2

ClinPred

0.89

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.55

gMVP

0.97

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