CLN6 p.Ser308Thr

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.923G>C(p.Ser308Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,557,662 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. S308R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:6

Conservation

PhyloP100: 0.754

Publications

9 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women's Health, G2P, 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

new If you want to explore the variant's impact on the transcript NM_017882.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010468572).

BP6

Variant 15-68208153-C-G is Benign according to our data. Variant chr15-68208153-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198573.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00162 (243/149982) while in subpopulation NFE AF = 0.0028 (189/67388). AF 95% confidence interval is 0.00248. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 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.923G>C	p.Ser308Thr	missense	Exon 7 of 7	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.1019G>C	p.Ser340Thr	missense	Exon 7 of 7	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.923G>C	p.Ser308Thr	missense	Exon 7 of 7	ENSP00000249806.5	Q9NWW5-1
CLN6	ENST00000566347.5	TSL:1	c.734G>C	p.Ser245Thr	missense	Exon 6 of 6	ENSP00000457783.1	H3BUT1
ENSG00000260007	ENST00000562767.2	TSL:3	c.84-10525G>C		intron	N/A	ENSP00000456336.1	H3BRN7

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

243

AN:

149868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000464

Gnomad AMI

AF:

0.00774

Gnomad AMR

AF:

0.000530

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00157

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00280

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.00186

AC:

466

AN:

250784

AF XY:

0.00185

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00236

Gnomad NFE exome

AF:

0.00349

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00241

AC:

3386

AN:

1407680

Hom.:

Cov.:

AF XY:

0.00228

AC XY:

1598

AN XY:

700652

show subpopulations

African (AFR)

AF:

0.000316

AC:

AN:

31654

American (AMR)

AF:

0.000116

AC:

AN:

43104

Ashkenazi Jewish (ASJ)

AF:

0.000209

AC:

AN:

23976

East Asian (EAS)

AF:

0.00

AC:

AN:

34208

South Asian (SAS)

AF:

0.00

AC:

AN:

85804

European-Finnish (FIN)

AF:

0.00267

AC:

130

AN:

48734

Middle Eastern (MID)

AF:

0.000186

AC:

AN:

5390

European-Non Finnish (NFE)

AF:

0.00292

AC:

3143

AN:

1078040

Other (OTH)

AF:

0.00162

AC:

AN:

56770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00162

AC:

243

AN:

149982

Hom.:

Cov.:

AF XY:

0.00142

AC XY:

104

AN XY:

73230

show subpopulations

African (AFR)

AF:

0.000463

AC:

AN:

41058

American (AMR)

AF:

0.000529

AC:

AN:

15112

Ashkenazi Jewish (ASJ)

AF:

0.000291

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

4936

South Asian (SAS)

AF:

0.00

AC:

AN:

4596

European-Finnish (FIN)

AF:

0.00157

AC:

AN:

10164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00280

AC:

189

AN:

67388

Other (OTH)

AF:

0.00144

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.00219

Hom.:

Bravo

AF:

0.00151

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Neuronal ceroid lipofuscinosis (2)

Adult neuronal ceroid lipofuscinosis;C5551375:Ceroid lipofuscinosis, neuronal, 6A (1)

Ceroid lipofuscinosis, neuronal, 6A;C5561927:Ceroid lipofuscinosis, neuronal, 6B (Kufs type) (1)

CLN6-related disorder (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

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.68

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

1.6

PhyloP100

0.75

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.91

REVEL

Uncertain

0.34

Sift

Benign

0.11

Sift4G

Benign

0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.090

gMVP

0.41

Mutation Taster

=97/3

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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