15-68208348-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_017882.3(CLN6):​c.728C>A​(p.Ala243Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CLN6
NM_017882.3 missense

Scores

9
8
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.76
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CLN6NM_017882.3 linkc.728C>A p.Ala243Asp missense_variant Exon 7 of 7 ENST00000249806.11 NP_060352.1 Q9NWW5-1A0A024R601
CLN6NM_001411068.1 linkc.824C>A p.Ala275Asp missense_variant Exon 7 of 7 NP_001397997.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CLN6ENST00000249806.11 linkc.728C>A p.Ala243Asp missense_variant Exon 7 of 7 1 NM_017882.3 ENSP00000249806.5 Q9NWW5-1
ENSG00000260007ENST00000562767.2 linkc.84-10720C>A intron_variant Intron 1 of 2 3 ENSP00000456336.1 H3BRN7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461652
Hom.:
0
Cov.:
38
AF XY:
0.00000138
AC XY:
1
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;D;D;.;T;T
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.83
D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.1
M;.;.;.;.;.
PrimateAI
Uncertain
0.66
T
PROVEAN
Uncertain
-4.2
D;D;D;D;.;.
REVEL
Pathogenic
0.89
Sift
Uncertain
0.012
D;D;D;D;.;.
Sift4G
Benign
0.085
T;D;T;T;.;.
Polyphen
1.0
D;.;.;.;.;.
Vest4
0.82
MutPred
0.56
.;.;.;Gain of relative solvent accessibility (P = 0.1259);.;.;
MVP
0.99
MPC
1.3
ClinPred
0.99
D
GERP RS
5.3
Varity_R
0.54
gMVP
0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-68500686; API