15-68207323-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_017882.3(CLN6):c.*817C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 152,448 control chromosomes in the GnomAD database, including 19,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.50 (19701 hom., cov: 34)
  • Exomes 𝑓: 0.54 (46 hom.)
• Consequence: CLN6 NM_017882.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.84

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-68207323-G-A is Benign according to our data. Variant chr15-68207323-G-A is described in ClinVar as [Benign]. Clinvar id is 316970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.552 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN6	NM_017882.3	c.*817C>T		3_prime_UTR_variant	7/7	ENST00000249806.11
CLN6	NM_001411068.1	c.*817C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11	c.*817C>T		3_prime_UTR_variant	7/7	1	NM_017882.3	P1
CLN6	ENST00000638076.1	c.*1356C>T		3_prime_UTR_variant, NMD_transcript_variant	7/7	1
CLN6	ENST00000636964.1	n.3281C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76286 AN: 152026 Hom.: 19684 Cov.: 34

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.515

GnomAD4 exome AF: 0.536 AC: 162 AN: 302 Hom.: 46 Cov.: 0 AF XY: 0.533 AC XY: 113 AN XY: 212

Gnomad4 AFR exome AF: 0.875

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.385

Gnomad4 NFE exome AF: 0.556

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.502 AC: 76338 AN: 152146 Hom.: 19701 Cov.: 34 AF XY: 0.494 AC XY: 36744 AN XY: 74366

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.502

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.176

Gnomad4 SAS AF: 0.349

Gnomad4 FIN AF: 0.513

Gnomad4 NFE AF: 0.556

Gnomad4 OTH AF: 0.510

Alfa AF: 0.503 Hom.: 6787

Bravo AF: 0.501

Asia WGS AF: 0.286 AC: 994 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.12
Dann	Benign	0.77

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

LitVar

Other links and lift over

dbSNP: rs8142; hg19: chr15-68499661;