15-68229580-T-C

Variant names:

• chr15-68229580-T-C
• rs3743088
• NM_017882.3:c.5A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

The NM_017882.3(CLN6):​c.5A>G​(p.Glu2Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,465,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 0.797

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]

ENSG00000260007 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_017882.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.012577295).
• BP6: Variant 15-68229580-T-C is Benign according to our data. Variant chr15-68229580-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 205179.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2, Benign=1}. Variant chr15-68229580-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000533 (81/151966) while in subpopulation EAS AF = 0.0114 (59/5160). AF 95% confidence interval is 0.0091. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN6	NM_017882.3	c.5A>G	p.Glu2Gly	missense_variant	Exon 1 of 7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.180-10930A>G		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.5A>G	p.Glu2Gly	missense_variant	Exon 1 of 7	1	NM_017882.3	ENSP00000249806.5
ENSG00000260007	ENST00000562767.2	c.5A>G	p.Glu2Gly	missense_variant	Exon 1 of 3	3		ENSP00000456336.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 151858 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000324 AC: 26 AN: 80306 AF XY: 0.000283

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000425

GnomAD4 exome AF: 0.000182 AC: 239 AN: 1313090 Hom.: 0 Cov.: 31 AF XY: 0.000184 AC XY: 119 AN XY: 647624

Gnomad4 AFR exome AF: 0.0000756 AC: 2 AN: 26458

Gnomad4 AMR exome AF: 0.0000371 AC: 1 AN: 26960

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 22894

Gnomad4 EAS exome AF: 0.00646 AC: 179 AN: 27724

Gnomad4 SAS exome AF: 0.000150 AC: 11 AN: 73104

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 32670

Gnomad4 NFE exome AF: 0.0000124 AC: 13 AN: 1044972

Gnomad4 Remaining exome AF: 0.000609 AC: 33 AN: 54160

GnomAD4 genome AF: 0.000533 AC: 81 AN: 151966 Hom.: 0 Cov.: 34 AF XY: 0.000633 AC XY: 47 AN XY: 74308

Gnomad4 AFR AF: 0.000434 AC: 0.000433777 AN: 0.000433777

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.0114 AC: 0.0114341 AN: 0.0114341

Gnomad4 SAS AF: 0.000207 AC: 0.000206954 AN: 0.000206954

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00142 AC: 0.0014245 AN: 0.0014245

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000676

ExAC AF: 0.0000809 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jul 27, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant of uncertain significance has been identified in the CLN6 gene. The E2G variant has beenreported previously in the homozygous state in an individual with late-infantile neuronal ceroidlipofuscinosis (Di Fruscio et al., 2015). The E2G variant is observed in 13/1008 (1.3%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). The E2G 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. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense variants in nearby residues (R5W, R6T) have been reported in the Human GeneMutation Database in association with NCL (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Jul 30, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 08, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Inborn genetic diseases Uncertain:1

Mar 26, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E2G variant (also known as c.5A>G), located in coding exon 1 of the CLN6 gene, results from an A to G substitution at nucleotide position 5. The glutamic acid at codon 2 is replaced by glycine, an amino acid with similar properties. This variant was reported as homozygous in an individual with neuronal ceroid lipofuscinosis (Di Fruscio G et al. Autophagy, 2015;11:928-38). This amino acid position is highly 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 Uncertain:1

Jan 25, 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. -

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

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ceroid lipofuscinosis, neuronal, 6B (Kufs type) Benign:1

Jul 27, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T;T;T;T;T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.50	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	1.6	.;L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.8	D;N;D;N;.;.;N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.016	.;D;D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;D;.
Polyphen		0.24	.;B;.;.;.;.;.;.
Vest4		0.39
MVP		0.88
MPC		0.10
ClinPred		0.079	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.27
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3743088; hg19: chr15-68521918;