15-68229551-C-T

Position:

chr15-68229551-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The ENST00000249806.11(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). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.010 ( 11 hom., cov: 34)

Exomes 𝑓: 0.016 ( 193 hom. )

Consequence

CLN6
ENST00000249806.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: 0.350

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in ENST00000249806.11

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: {Benign=8, Uncertain_significance=1, Likely_benign=3}. 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 linkuse as main transcript	c.34G>A	p.Ala12Thr	missense_variant	1/7	ENST00000249806.11	NP_060352.1
CLN6	NM_001411068.1 linkuse as main transcript	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 linkuse as main transcript	c.34G>A	p.Ala12Thr	missense_variant	1/7	1	NM_017882.3	ENSP00000249806	P1	Q9NWW5-1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1577

AN:

151956

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00990

AC XY:

463

AN XY:

46784

show subpopulations

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.:

AF XY:

0.0159

AC XY:

10304

AN XY:

649704

show subpopulations

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.:

Cov.:

AF XY:

0.00954

AC XY:

709

AN XY:

74350

show subpopulations

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.:

Bravo

AF:

0.0103

ExAC

AF:

0.00293

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CLN6: PP3, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Neuronal ceroid lipofuscinosis

Uncertain:1Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:3

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

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

BayesDel_noAF

Uncertain

0.10

CADD

Benign

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

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

MutationAssessor

Benign

1.2

.;L;.;.;.;.;.;.

MutationTaster

Benign

0.52

D;D;D;D;N;N

PrimateAI

Pathogenic

0.84

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over