rs117038427

Positions:

chr15-68211869-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 128785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-68211869-G-A is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3 linkuse as main transcript	c.298-6C>T		splice_region_variant, intron_variant		ENST00000249806.11	NP_060352.1	Q9NWW5-1A0A024R601
CLN6	NM_001411068.1 linkuse as main transcript	c.394-6C>T		splice_region_variant, intron_variant			NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11 linkuse as main transcript	c.298-6C>T		splice_region_variant, intron_variant		1	NM_017882.3	ENSP00000249806.5		Q9NWW5-1
ENSG00000260007	ENST00000562767.2 linkuse as main transcript	c.84-14241C>T		intron_variant		3		ENSP00000456336.1		H3BRN7

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

GnomAD3 exomes

AF:

0.00770

AC:

1923

AN:

249610

Hom.:

AF XY:

0.00810

AC XY:

1093

AN XY:

134970

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 SAS exome

AF:

0.0100

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

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00344

Gnomad4 ASJ exome

AF:

0.00846

Gnomad4 EAS exome

AF:

0.0353

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.000908

Gnomad4 NFE exome

AF:

0.00832

Gnomad4 OTH exome

AF:

0.00835

GnomAD4 genome

AF:

0.00608

AC:

926

AN:

152244

Hom.:

Cov.:

AF XY:

0.00574

AC XY:

427

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00340

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.0319

Gnomad4 SAS

AF:

0.00974

Gnomad4 FIN

AF:

0.000943

Gnomad4 NFE

AF:

0.00773

Gnomad4 OTH

AF:

0.00900

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

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2019	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Neuronal ceroid lipofuscinosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.85

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

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