Genetic Variant CLN6:p.Val245Phe (chr15-68208343-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_017882.3(CLN6):c.733G>T(p.Val245Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V245I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CLN6
NM_017882.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.12

Publications

0 publications found

Variant links:

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

CLN6 links:

ENSG00000260007 (HGNC:):

ENSG00000260007 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_017882.3

PM2

Very rare variant in population databases, with high coverage;

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN6	NM_017882.3	MANE Select	c.733G>T	p.Val245Phe	missense	Exon 7 of 7	NP_060352.1
	CLN6	NM_001411068.1		c.829G>T	p.Val277Phe	missense	Exon 7 of 7	NP_001397997.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CLN6	ENST00000249806.11	TSL:1 MANE Select	c.733G>T	p.Val245Phe	missense	Exon 7 of 7	ENSP00000249806.5
CLN6	ENST00000637667.1	TSL:1	c.634G>T	p.Val212Phe	missense	Exon 6 of 6	ENSP00000489843.1
CLN6	ENST00000566347.5	TSL:1	c.544G>T	p.Val182Phe	missense	Exon 6 of 6	ENSP00000457783.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.74

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.7

PhyloP100

3.1

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.76

Sift

Benign

0.071

Sift4G

Benign

0.075

Polyphen

0.18

Vest4

0.74

MVP

0.96

MPC

0.99

ClinPred

0.97

GERP RS

5.2

Varity_R

0.17

gMVP

0.93

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over