rs154774636

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_017882.3(CLN6):c.17G>C(p.Arg6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,315,504 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000023 ( 0 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 0.370

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

ceroid lipofuscinosis, neuronal, 6A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Orphanet
ceroid lipofuscinosis, neuronal, 6B (Kufs type)
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

CLN6 links:

ENSG00000260007 (HGNC:):

ENSG00000260007 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-68229568-C-G is Pathogenic according to our data. Variant chr15-68229568-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 30602.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3 link	c.17G>C	p.Arg6Thr	missense_variant	Exon 1 of 7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1 link	c.180-10918G>C		intron_variant	Intron 1 of 6		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 link	c.17G>C	p.Arg6Thr	missense_variant	Exon 1 of 7	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2 link	c.17G>C	p.Arg6Thr	missense_variant	Exon 1 of 3	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000123

AC:

AN:

81494

AF XY:

0.0000215

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000341

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000228

AC:

AN:

1315504

Hom.:

Cov.:

AF XY:

0.00000308

AC XY:

AN XY:

648824

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26504

American (AMR)

AF:

0.00

AC:

AN:

27244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22964

East Asian (EAS)

AF:

0.00

AC:

AN:

27956

South Asian (SAS)

AF:

0.00

AC:

AN:

73282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32700

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.00000287

AC:

AN:

1046430

Other (OTH)

AF:

0.00

AC:

AN:

54310

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0662318), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Ceroid lipofuscinosis, neuronal, 6B (Kufs type)

Pathogenic:1

May 13, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Other:1

SNPedia

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.56

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

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.81

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

M_CAP

Pathogenic

0.99

MetaRNN

Uncertain

0.50

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

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.5

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

PhyloP100

0.37

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.0

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

REVEL

Uncertain

0.63

Sift

Uncertain

0.0090

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.13

.;B;.;.;.;.;.;.

Vest4

0.36

MutPred

0.20

Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);Loss of MoRF binding (P = 0.0149);

MVP

0.86

MPC

0.13

ClinPred

0.96

GERP RS

2.4

PromoterAI

0.093

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.19

gMVP

0.36

Mutation Taster

=17/83

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over