rs886051439

Variant names:

• chr15-68207840-G-A
• rs886051439
• NM_017882.3:c.*300C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017882.3(CLN6):​c.*300C>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 0.00000892 in 448,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CLN6 NM_017882.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.161
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• ceroid lipofuscinosis, neuronal, 6A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• ceroid lipofuscinosis, neuronal, 6B (Kufs type)

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017882.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	NM_017882.3	MANE Select	c.*300C>T		3_prime_UTR	Exon 7 of 7	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.*300C>T		3_prime_UTR	Exon 7 of 7	NP_001397997.1	Q9NWW5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	ENST00000249806.11	TSL:1 MANE Select	c.*300C>T		3_prime_UTR	Exon 7 of 7	ENSP00000249806.5	Q9NWW5-1
	ENSG00000260007	ENST00000562767.2	TSL:3	c.84-10212C>T		intron	N/A	ENSP00000456336.1	H3BRN7
	CLN6	ENST00000638076.1	TSL:1	n.*839C>T		non_coding_transcript_exon	Exon 7 of 7	ENSP00000490373.1	A0A0S2Z5D0

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000101 AC: 3 AN: 296570 Hom.: 0 Cov.: 0 AF XY: 0.00000631 AC XY: 1 AN XY: 158436

African (AFR) AF: 0.000115 AC: 1 AN: 8700

American (AMR) AF: 0.0000729 AC: 1 AN: 13716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8656

East Asian (EAS) AF: 0.00 AC: 0 AN: 16982

South Asian (SAS) AF: 0.00 AC: 0 AN: 43152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1208

European-Non Finnish (NFE) AF: 0.00000576 AC: 1 AN: 173732

Other (OTH) AF: 0.00 AC: 0 AN: 16140

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74278

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuronal ceroid lipofuscinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.95
DANN	Benign	0.71
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs886051439; hg19: chr15-68500178;