rs112239768

Positions:

• chr15-68229551-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017882.3(CLN6):​c.34G>A​(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,469,292 control chromosomes in the GnomAD database, including 204 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 0.010 (11 hom., cov: 34)
  • Exomes 𝑓: 0.016 (193 hom.)
• Consequence: CLN6 NM_017882.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:13
• Conservation: PhyloP100: 0.350

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007892162).
• BP6: Variant 15-68229551-C-T is Benign according to our data. Variant chr15-68229551-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136802.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=8, Uncertain_significance=1}. Variant chr15-68229551-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1578/152064) while in subpopulation NFE AF= 0.0179 (1216/67934). AF 95% confidence interval is 0.0171. There are 11 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN6	NM_017882.3	c.34G>A	p.Ala12Thr	missense_variant	1/7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1	c.180-10901G>A		intron_variant			NP_001397997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN6	ENST00000249806.11	c.34G>A	p.Ala12Thr	missense_variant	1/7	1	NM_017882.3	ENSP00000249806	P1

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1577 AN: 151956 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00165

Gnomad FIN AF: 0.00656

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0179

Gnomad OTH AF: 0.00816

GnomAD3 exomes AF: 0.0100 AC: 820 AN: 82002 Hom.: 9 AF XY: 0.00990 AC XY: 463 AN XY: 46784

Gnomad AFR exome AF: 0.00309

Gnomad AMR exome AF: 0.00614

Gnomad ASJ exome AF: 0.00767

Gnomad EAS exome AF: 0.000273

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.00677

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0165 AC: 21701 AN: 1317228 Hom.: 193 Cov.: 31 AF XY: 0.0159 AC XY: 10304 AN XY: 649704

Gnomad4 AFR exome AF: 0.00226

Gnomad4 AMR exome AF: 0.00663

Gnomad4 ASJ exome AF: 0.00735

Gnomad4 EAS exome AF: 0.0000354

Gnomad4 SAS exome AF: 0.00289

Gnomad4 FIN exome AF: 0.00593

Gnomad4 NFE exome AF: 0.0192

Gnomad4 OTH exome AF: 0.0137

GnomAD4 genome AF: 0.0104 AC: 1578 AN: 152064 Hom.: 11 Cov.: 34 AF XY: 0.00954 AC XY: 709 AN XY: 74350

Gnomad4 AFR AF: 0.00332

Gnomad4 AMR AF: 0.00648

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00656

Gnomad4 NFE AF: 0.0179

Gnomad4 OTH AF: 0.00760

Alfa AF: 0.0134 Hom.: 1

Bravo AF: 0.0103

ExAC AF: 0.00293 AC: 69

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2018	This variant is associated with the following publications: (PMID: 21990111, 29482223) -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CLN6: PP3, BS1, BS2 -

Neuronal ceroid lipofuscinosis Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 29, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ceroid lipofuscinosis, neuronal, 6A Benign:1

Benign, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

May 31, 2018

This variant is interpreted as a Benign, for Ceroid lipofuscinosis, neuronal, 6, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

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

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2021

CLN6 NM_017882.2 p.Ala12Thr (c.34G>A): This variant has been reported in the literature in at least 2 individuals (1 with neuronal ceroid lipofuscinosis and 1 with cerebellar ataxia) (Kousi 2012 PMID:21990111, Coutelier 2018 PMID:29482223). However, this variant is present in 1.7% (1216/67944) of European alleles including 11 homozygotes in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/15-68229551-C-T?dataset=gnomad_r3). Evolutionary conservation and computational predictive tools for this variant are unclear. This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:136802). In summary, data on this variant suggests that this variant does not cause disease, but requires further evidence. Therefore this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Uncertain	0.10
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;T;T;T;T;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0079	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.2	.;L;.;.;.;.;.;.
MutationTaster	Benign	0.52	D;D;D;D;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.0	D;N;N;N;.;.;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.059	.;T;D;T;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;.;D;.
Polyphen		0.030	.;B;.;.;.;.;.;.
Vest4		0.18
MVP		0.81
MPC		0.084
ClinPred		0.017	T
GERP RS		1.3
Varity_R		0.047
gMVP		0.35

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: rs112239768; hg19: chr15-68521889;