15-68214302-AAA-CAG

Variant names:

• chr15-68214302-AAA-CAG
• NM_017882.3:c.283_285delTTTinsCTG
• CLN6 p.Phe95Leu

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_017882.3(CLN6):​c.283_285delTTTinsCTG​(p.Phe95Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F95S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.91
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_017882.3
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.283_285delTTTinsCTG	p.Phe95Leu	missense	N/A	NP_060352.1	Q9NWW5-1
	CLN6	NM_001411068.1		c.379_381delTTTinsCTG	p.Phe127Leu	missense	N/A	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.283_285delTTTinsCTG	p.Phe95Leu	missense	N/A	ENSP00000249806.5	Q9NWW5-1
	CLN6	ENST00000566347.5	TSL:1	c.283_285delTTTinsCTG	p.Phe95Leu	missense	N/A	ENSP00000457783.1	H3BUT1
	CLN6	ENST00000637667.1	TSL:1	c.199-2441_199-2439delTTTinsCTG		intron	N/A	ENSP00000489843.1	A0A1B0GTU6

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-68506640;