rs117038427

Positions:

• chr15-68211869-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017882.3(CLN6):​c.298-6C>T variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.005652
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.79

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]

ACMG classification

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	UniProt
CLN6	NM_017882.3	c.298-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000249806.11
CLN6	NM_001411068.1	c.394-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11	c.298-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_017882.3	P1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 927 AN: 152126 Hom.: 4 Cov.: 32

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.: 9 AF XY: 0.00810 AC XY: 1093 AN XY: 134970

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.: 82 Cov.: 32 AF XY: 0.00859 AC XY: 6245 AN XY: 726634

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.: 4 Cov.: 32 AF XY: 0.00574 AC XY: 427 AN XY: 74432

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.: 3

Bravo AF: 0.00637

Asia WGS AF: 0.0180 AC: 62 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

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	Eurofins Ntd Llc (ga)	Apr 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

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

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	Invitae	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	13
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

Other links and lift over

dbSNP: rs117038427; hg19: chr15-68504207; COSMIC: COSV51117630; COSMIC: COSV51117630;