15-68207450-T-C

Position:

• chr15-68207450-T-C

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.*690A>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 0.0667 in 155,454 control chromosomes in the GnomAD database, including 971 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (971 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (0 hom.)
• Consequence: CLN6 NM_017882.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.657

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=-0.94).
• BP6: Variant 15-68207450-T-C is Benign according to our data. Variant chr15-68207450-T-C is described in ClinVar as [Benign]. Clinvar id is 316972.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3	c.*690A>G		3_prime_UTR_variant	7/7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.*690A>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.*690A>G		3_prime_UTR_variant	7/7	1	NM_017882.3	ENSP00000249806	P1
CLN6	ENST00000638076.1	c.*1229A>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	1		ENSP00000490373
CLN6	ENST00000636964.1	n.3154A>G		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10323 AN: 152026 Hom.: 967 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0327

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.0365

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00883

Gnomad OTH AF: 0.0554

GnomAD4 exome AF: 0.00755 AC: 25 AN: 3310 Hom.: 0 Cov.: 0 AF XY: 0.00833 AC XY: 15 AN XY: 1800

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00680

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00645

Gnomad4 OTH exome AF: 0.00926

GnomAD4 genome AF: 0.0680 AC: 10351 AN: 152144 Hom.: 971 Cov.: 33 AF XY: 0.0650 AC XY: 4832 AN XY: 74394

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.0326

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.0366

Gnomad4 SAS AF: 0.0110

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00881

Gnomad4 OTH AF: 0.0562

Alfa AF: 0.0208 Hom.: 141

Bravo AF: 0.0778

Asia WGS AF: 0.0380 AC: 134 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.1
DANN	Benign	0.46

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: rs8033190; hg19: chr15-68499788;