rs3743088

chr15-68229580-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM2 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:5 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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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
• PM2: Very rare variant in population databases, with high coverage
• 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: {Benign=1, Uncertain_significance=5, Likely_benign=2}. 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 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.5A>G	p.Glu2Gly	missense_variant	1/7	ENST00000249806.11
CLN6	NM_001411068.1	c.180-10930A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLN6	ENST00000249806.11	c.5A>G	p.Glu2Gly	missense_variant	1/7	1	NM_017882.3	P1

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

GnomAD3 exomes AF: 0.000324 AC: 26 AN: 80306 Hom.: 1 AF XY: 0.000283 AC XY: 13 AN XY: 45872

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 SAS exome AF: 0.00

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

Gnomad4 AMR exome AF: 0.0000371

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00646

Gnomad4 SAS exome AF: 0.000150

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000124

Gnomad4 OTH exome AF: 0.000609

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

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

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:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 27, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 30, 2020	- -

Neuronal ceroid lipofuscinosis Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 08, 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. 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2019

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

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 25, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 27, 2020

- -

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
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
MutationTaster	Benign	1.0	D;D;N;N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.8	D;N;D;N;.;.;N;.
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

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;