15-68207494-G-C

Position:

• chr15-68207494-G-C

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.*646C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 163,172 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (2 hom.)
• Consequence: CLN6 NM_017882.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.232

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=-0.92).
• BP6: Variant 15-68207494-G-C is Benign according to our data. Variant chr15-68207494-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 316974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00552 (841/152238) while in subpopulation AMR AF= 0.0113 (173/15294). AF 95% confidence interval is 0.00994. There are 5 homozygotes in gnomad4. There are 428 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3	c.*646C>G		3_prime_UTR_variant	7/7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.*646C>G		3_prime_UTR_variant	7/7		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.*646C>G		3_prime_UTR_variant	7/7	1	NM_017882.3	ENSP00000249806	P1
CLN6	ENST00000638076.1	c.*1185C>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	1		ENSP00000490373
CLN6	ENST00000636964.1	n.3110C>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 841 AN: 152120 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00817

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00622 AC: 68 AN: 10934 Hom.: 2 Cov.: 0 AF XY: 0.00586 AC XY: 34 AN XY: 5800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00826

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000643

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00723

Gnomad4 OTH exome AF: 0.00985

GnomAD4 genome AF: 0.00552 AC: 841 AN: 152238 Hom.: 5 Cov.: 33 AF XY: 0.00575 AC XY: 428 AN XY: 74434

Gnomad4 AFR AF: 0.00166

Gnomad4 AMR AF: 0.0113

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00818

Gnomad4 OTH AF: 0.00757

Alfa AF: 0.00112 Hom.: 0

Bravo AF: 0.00598

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Neuronal ceroid lipofuscinosis Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.18
DANN	Benign	0.54

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: rs144976448; hg19: chr15-68499832;