rs763944821
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_017882.3(CLN6):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,467,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00023 ( 9 hom. )
Consequence
CLN6
NM_017882.3 missense
NM_017882.3 missense
Scores
5
3
11
Clinical Significance
Conservation
PhyloP100: 0.996
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 Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.014074415).
BP6
Variant 15-68229536-C-T is Benign according to our data. Variant chr15-68229536-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205180.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=4}. Variant chr15-68229536-C-T is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00023 (303/1315828) while in subpopulation SAS AF= 0.00362 (265/73256). AF 95% confidence interval is 0.00326. There are 9 homozygotes in gnomad4_exome. There are 224 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 9 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CLN6 | NM_017882.3 | c.49G>A | p.Gly17Ser | missense_variant | 1/7 | ENST00000249806.11 | NP_060352.1 | |
CLN6 | NM_001411068.1 | c.180-10886G>A | intron_variant | NP_001397997.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CLN6 | ENST00000249806.11 | c.49G>A | p.Gly17Ser | missense_variant | 1/7 | 1 | NM_017882.3 | ENSP00000249806 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000132 AC: 20AN: 151974Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000825 AC: 67AN: 81240Hom.: 2 AF XY: 0.00114 AC XY: 53AN XY: 46378
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GnomAD4 exome AF: 0.000230 AC: 303AN: 1315828Hom.: 9 Cov.: 31 AF XY: 0.000345 AC XY: 224AN XY: 648858
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GnomAD4 genome AF: 0.000132 AC: 20AN: 152082Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14AN XY: 74360
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CLN6 p.Gly17Ser variant was identified in a patient from Turkey with neuronal ceroid lipofuscinose (Kousi_2012_PMID:21990111). The variant was identified in dbSNP (ID: rs763944821) and ClinVar (classified as benign by Invitae and as a VUS by Counsyl, Ambry Genetics and GeneDx) but was not identified in LOVD 3.0. The variant was identified in control databases in 68 of 112310 chromosomes (2 homozygous) at a frequency of 0.0006055 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 67 of 17028 chromosomes (freq: 0.003935) and Other in 1 of 3468 chromosomes (freq: 0.000288), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and European (non-Finnish) populations. The p.Gly17 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 12, 2018 | p.Gly17Ser (GGC>AGC): c.49 G>A in exon 1 of the CLN6 gene (NM_017882.2). The G17S missense substitution was reported as a novel disease-causing mutation (Kousi et al., 2012); however, it was identified in a patient who did not have a second detectable mutation in the CLN6 gene, and no additional information was provided about the patient's phenotype. G17S was not observed in approximately 1,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G17S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts the G17S variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). - |
Neuronal ceroid lipofuscinosis Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 26, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2020 | The p.G17S variant (also known as c.49G>A), located in coding exon 1 of the CLN6 gene, results from a G to A substitution at nucleotide position 49. The glycine at codon 17 is replaced by serine, an amino acid with similar properties. This alteration was reported as a novel disease-causing mutation in the heterozygous state in one individual; however, a second alteration was not reported and no clinical information was provided for this individual (Kousi M et al. Hum. Mutat., 2012 Jan;33:42-63). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ceroid lipofuscinosis, neuronal, 6A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 05, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 20, 2022 | Variant summary: CLN6 c.49G>A (p.Gly17Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 81240 control chromosomes, predominantly at a frequency of 0.0039 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CLN6 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.49G>A has been reported in the literature in at least one individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Kousi_2012). The report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;T;T;T;T;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;T;T;T;T
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;L;.;.;.;.;.;.
MutationTaster
Benign
N;N;N;N;N;N
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;N;N;N;.;.;N;.
REVEL
Uncertain
Sift
Benign
.;T;D;T;.;.;T;.
Sift4G
Pathogenic
D;T;D;T;.;.;T;.
Polyphen
0.0
.;B;.;.;.;.;.;.
Vest4
MutPred
Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);Gain of stability (P = 0.0811);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at