rs117038427

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_017882.3(CLN6):c.298-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00839 in 1,613,084 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0061 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 82 hom. )

Consequence

CLN6
NM_017882.3 splice_region, intron

Scores

Splicing: ADA: 0.005652

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.79

Publications

4 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 15-68211869-G-A is Benign according to our data. Variant chr15-68211869-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00608 (926/152244) while in subpopulation EAS AF = 0.0319 (165/5172). AF 95% confidence interval is 0.0279. There are 4 homozygotes in GnomAd4. There are 427 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 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.298-6C>T		splice_region intron	N/A	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.394-6C>T		splice_region intron	N/A	NP_001397997.1	Q9NWW5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLN6	ENST00000249806.11	TSL:1 MANE Select	c.298-6C>T	splice_region intron	N/A	ENSP00000249806.5	Q9NWW5-1
CLN6	ENST00000637667.1	TSL:1	c.199-6C>T	splice_region intron	N/A	ENSP00000489843.1	A0A1B0GTU6
CLN6	ENST00000566347.5	TSL:1	c.298-551C>T	intron	N/A	ENSP00000457783.1	H3BUT1

Frequencies

GnomAD3 genomes

AF:

0.00609

AC:

927

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.0318

Gnomad SAS

AF:

0.00994

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00773

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00770

AC:

1923

AN:

249610

AF XY:

0.00810

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00350

Gnomad ASJ exome

AF:

0.00728

Gnomad EAS exome

AF:

0.0310

Gnomad FIN exome

AF:

0.000996

Gnomad NFE exome

AF:

0.00688

Gnomad OTH exome

AF:

0.00608

GnomAD4 exome

AF:

0.00863

AC:

12603

AN:

1460840

Hom.:

Cov.:

AF XY:

0.00859

AC XY:

6245

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.00122

AC:

AN:

33474

American (AMR)

AF:

0.00344

AC:

154

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00846

AC:

221

AN:

26124

East Asian (EAS)

AF:

0.0353

AC:

1403

AN:

39694

South Asian (SAS)

AF:

0.0112

AC:

969

AN:

86236

European-Finnish (FIN)

AF:

0.000908

AC:

AN:

52858

Middle Eastern (MID)

AF:

0.00270

AC:

AN:

5554

European-Non Finnish (NFE)

AF:

0.00832

AC:

9248

AN:

1111844

Other (OTH)

AF:

0.00835

AC:

504

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

613

1226

1840

2453

3066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.00608

AC:

926

AN:

152244

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

427

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

41536

American (AMR)

AF:

0.00340

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.0319

AC:

165

AN:

5172

South Asian (SAS)

AF:

0.00974

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00773

AC:

526

AN:

68012

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00657

Hom.:

Bravo

AF:

0.00637

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.00654

EpiControl

AF:

0.00688

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Neuronal ceroid lipofuscinosis (2)

not provided (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0057

dbscSNV1_RF

Benign

0.068

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