rs143578698

chr15-68208153-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_017882.3(CLN6):c.923G>C(p.Ser308Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,557,662 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S308S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (9 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:5
• Conservation: PhyloP100: 0.754

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010468572).
• BP6: Variant 15-68208153-C-G is Benign according to our data. Variant chr15-68208153-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198573.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=2, Benign=1}. Variant chr15-68208153-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00162 (243/149982) while in subpopulation NFE AF= 0.0028 (189/67388). AF 95% confidence interval is 0.00248. There are 1 homozygotes in gnomad4. There are 104 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLN6	NM_017882.3	c.923G>C	p.Ser308Thr	missense_variant	7/7	ENST00000249806.11
CLN6	NM_001411068.1	c.1019G>C	p.Ser340Thr	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11	c.923G>C	p.Ser308Thr	missense_variant	7/7	1	NM_017882.3	P1

Frequencies

GnomAD3 genomes AF: 0.00162 AC: 243 AN: 149868 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000464

Gnomad AMI AF: 0.00774

Gnomad AMR AF: 0.000530

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00157

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00280

Gnomad OTH AF: 0.00145

GnomAD3 exomes AF: 0.00186 AC: 466 AN: 250784 Hom.: 1 AF XY: 0.00185 AC XY: 251 AN XY: 135684

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00241 AC: 3386 AN: 1407680 Hom.: 9 Cov.: 39 AF XY: 0.00228 AC XY: 1598 AN XY: 700652

Gnomad4 AFR exome AF: 0.000316

Gnomad4 AMR exome AF: 0.000116

Gnomad4 ASJ exome AF: 0.000209

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00267

Gnomad4 NFE exome AF: 0.00292

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00162 AC: 243 AN: 149982 Hom.: 1 Cov.: 31 AF XY: 0.00142 AC XY: 104 AN XY: 73230

Gnomad4 AFR AF: 0.000463

Gnomad4 AMR AF: 0.000529

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00157

Gnomad4 NFE AF: 0.00280

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00219 Hom.: 0

Bravo AF: 0.00151

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00237 AC: 288

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2020	This variant is associated with the following publications: (PMID: 25359263, 30548430, 21549341) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CLN6: BS2 -

Neuronal ceroid lipofuscinosis Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 16, 2016

- -

CLN6-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2023

The CLN6 c.923G>C variant is predicted to result in the amino acid substitution p.Ser308Thr. This variant has been previously reported along with two other variants in the CLN6 gene in an individual with major adult form of neuronal ceroid lipofuscinosis (Family Ku8, Arsov et al. 2011. PubMed ID: 21549341). This variant was also observed in the heterozygous state in a cohort of individuals with suspected lysosomal storage disease and reported as a variant of uncertain significance (Table 3, Gheldof et al. 2019. PubMed ID: 30548430). This variant is reported in 0.34% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-68500491-C-G), which is more common than expected for a primary cause of disease. Although we suspect this variant may be benign, at this time, the clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2018

The p.S308T variant (also known as c.923G>C), located in coding exon 7 of the CLN6 gene, results from a G to C substitution at nucleotide position 923. The serine at codon 308 is replaced by threonine, an amino acid with similar properties. In one study, this alteration was detected in conjunction with two additional CLN6 alterations c.150C>G (p.T50*) and c.231C>G (p.N77K) in an individual with Kufs disease; however, the phase of these three alterations was not confirmed (Arsov T et al. Am. J. Hum. Genet., 2011 May;88:566-73). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ceroid lipofuscinosis, neuronal, 6A;C5561927:Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

CLN6 NM_017882.2 exon 7 p.Ser308Thr (c.923G>C): This variant has not been reported in the literature and is present in 0.3% (435/128540) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-68500491-C-G). This variant is present in ClinVar (Variation ID:198573). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Adult neuronal ceroid lipofuscinosis;C5551375:Ceroid lipofuscinosis, neuronal, 6A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;T;T;.;T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.68	T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.6	L;.;.;.;.
MutationTaster	Benign	0.84	D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.91	N;N;N;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;T;T;D;.
Sift4G	Benign	0.26	T;T;T;T;.
Polyphen		0.37	B;.;.;.;.
Vest4		0.20
MVP		0.93
MPC		0.31
ClinPred		0.017	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.41

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

LitVar

Other links and lift over

dbSNP: rs143578698; hg19: chr15-68500491; COSMIC: COSV99031557; COSMIC: COSV99031557;