NM_017882.3:c.49G>A

Variant names:

• chr15-68229536-C-T
• rs763944821
• NM_017882.3:c.49G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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). Synonymous variant affecting the same amino acid position (i.e. G17G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (9 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.996
• Publications: 5 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, 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

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 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 GnomAdExome4. There are 224 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.180-10886G>A		intron_variant	Intron 1 of 6		NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 7	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2	c.49G>A	p.Gly17Ser	missense_variant	Exon 1 of 3	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151974 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000825 AC: 67 AN: 81240 AF XY: 0.00114

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000230 AC: 303 AN: 1315828 Hom.: 9 Cov.: 31 AF XY: 0.000345 AC XY: 224 AN XY: 648858

African (AFR) AF: 0.00 AC: 0 AN: 26476

American (AMR) AF: 0.0000737 AC: 2 AN: 27148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22928

East Asian (EAS) AF: 0.00 AC: 0 AN: 28188

South Asian (SAS) AF: 0.00362 AC: 265 AN: 73256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32654

Middle Eastern (MID) AF: 0.000755 AC: 3 AN: 3976

European-Non Finnish (NFE) AF: 0.0000239 AC: 25 AN: 1046858

Other (OTH) AF: 0.000147 AC: 8 AN: 54344

GnomAD4 genome AF: 0.000132 AC: 20 AN: 152082 Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000145 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00124 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Nov 12, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Neuronal ceroid lipofuscinosis Uncertain:1 Benign:1

Sep 26, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Jan 06, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 05, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified Benign:1

Apr 20, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Pathogenic	0.15
CADD	Benign	9.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	.;T;T;T;T;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Benign	0.014	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.4	.;L;.;.;.;.;.;.
PhyloP100		1.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.0	D;N;N;N;.;.;N;.
REVEL	Uncertain	0.54
Sift	Benign	0.71	.;T;D;T;.;.;T;.
Sift4G	Pathogenic	0.0	D;T;D;T;.;.;T;.
Polyphen		0.0	.;B;.;.;.;.;.;.
Vest4		0.20
MutPred		0.13		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		0.54
MPC		0.086
ClinPred		0.069	T
GERP RS		2.1
PromoterAI		0.081	Neutral
Varity_R		0.050
gMVP		0.34
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs763944821; hg19: chr15-68521874;