rs763944821

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017882.3(CLN6):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,467,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G17G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00023 ( 9 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: 0.996

Publications

5 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, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
ceroid lipofuscinosis, neuronal, 6B (Kufs type)
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014074415).

BP6

Variant 15-68229536-C-T is Benign according to our data. Variant chr15-68229536-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 205180.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00023 (303/1315828) while in subpopulation SAS AF = 0.00362 (265/73256). AF 95% confidence interval is 0.00326. There are 9 homozygotes in GnomAdExome4. There are 224 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	NM_017882.3	MANE Select	c.49G>A	p.Gly17Ser	missense	Exon 1 of 7	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.180-10886G>A		intron	N/A	NP_001397997.1	Q9NWW5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLN6	ENST00000249806.11	TSL:1 MANE Select	c.49G>A	p.Gly17Ser	missense	Exon 1 of 7	ENSP00000249806.5	Q9NWW5-1
CLN6	ENST00000637667.1	TSL:1	c.49G>A	p.Gly17Ser	missense	Exon 1 of 6	ENSP00000489843.1	A0A1B0GTU6
CLN6	ENST00000566347.5	TSL:1	c.49G>A	p.Gly17Ser	missense	Exon 1 of 6	ENSP00000457783.1	H3BUT1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000825

AC:

AN:

81240

AF XY:

0.00114

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000230

AC:

303

AN:

1315828

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

224

AN XY:

648858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26476

American (AMR)

AF:

0.0000737

AC:

AN:

27148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22928

East Asian (EAS)

AF:

0.00

AC:

AN:

28188

South Asian (SAS)

AF:

0.00362

AC:

265

AN:

73256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32654

Middle Eastern (MID)

AF:

0.000755

AC:

AN:

3976

European-Non Finnish (NFE)

AF:

0.0000239

AC:

AN:

1046858

Other (OTH)

AF:

0.000147

AC:

AN:

54344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000132

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00331

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67950

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000145

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00124

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neuronal ceroid lipofuscinosis (2)

not provided (2)

Ceroid lipofuscinosis, neuronal, 6A (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

9.6

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.014

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

1.4

PhyloP100

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.54

Sift

Benign

0.71

Sift4G

Pathogenic

0.0

Polyphen

0.0

Vest4

0.20

MutPred

0.13

Gain of stability (P = 0.0811)

MVP

0.54

MPC

0.086

ClinPred

0.069

GERP RS

2.1

PromoterAI

0.081

Neutral

(source)

Varity_R

0.050

gMVP

0.34

Mutation Taster

=90/10

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over