Genetic Variant CLN8:c.543+2997G>T (chr8-1774594-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_018941.4(CLN8):c.543+2997G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 152,154 control chromosomes in the GnomAD database, including 52,000 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.82 ( 52000 hom., cov: 32)

Consequence

CLN8
NM_018941.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.126

Publications

5 publications found

Variant links:

Genes affected

CLN8 (HGNC:2079): (CLN8 transmembrane ER and ERGIC protein) This gene encodes a transmembrane protein belonging to a family of proteins containing TLC domains, which are postulated to function in lipid synthesis, transport, or sensing. The protein localizes to the endoplasmic reticulum (ER), and may recycle between the ER and ER-Golgi intermediate compartment. Mutations in this gene are associated with a disorder characterized by progressive epilepsy with cognitive disabilities (EPMR), which is a subtype of neuronal ceroid lipofuscinoses (NCL). Patients with mutations in this gene have altered levels of sphingolipid and phospholipids in the brain. [provided by RefSeq, Jul 2017]

CLN8 Gene-Disease associations (from GenCC):

neuronal ceroid lipofuscinosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
neuronal ceroid lipofuscinosis 8
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Myriad Women’s Health
neuronal ceroid lipofuscinosis 8 northern epilepsy variant
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
autism spectrum disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

CLN8 links:

KBTBD11-OT1 (HGNC:):

KBTBD11-OT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN8	NM_018941.4 link	c.543+2997G>T		intron_variant	Intron 2 of 2	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6 link	c.543+2997G>T		intron_variant	Intron 2 of 2	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1 link	n.543+2997G>T		intron_variant	Intron 2 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes

AF:

0.823

AC:

125183

AN:

152036

Hom.:

51943

Cov.:

show subpopulations

Gnomad AFR

AF:

0.906

Gnomad AMI

AF:

0.909

Gnomad AMR

AF:

0.671

Gnomad ASJ

AF:

0.765

Gnomad EAS

AF:

0.758

Gnomad SAS

AF:

0.780

Gnomad FIN

AF:

0.824

Gnomad MID

AF:

0.793

Gnomad NFE

AF:

0.818

Gnomad OTH

AF:

0.809

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.823

AC:

125292

AN:

152154

Hom.:

52000

Cov.:

AF XY:

0.819

AC XY:

60956

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.906

AC:

37619

AN:

41524

American (AMR)

AF:

0.670

AC:

10237

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.765

AC:

2655

AN:

3470

East Asian (EAS)

AF:

0.759

AC:

3911

AN:

5154

South Asian (SAS)

AF:

0.780

AC:

3759

AN:

4818

European-Finnish (FIN)

AF:

0.824

AC:

8723

AN:

10590

Middle Eastern (MID)

AF:

0.781

AC:

228

AN:

292

European-Non Finnish (NFE)

AF:

0.818

AC:

55618

AN:

67996

Other (OTH)

AF:

0.810

AC:

1715

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1126

2252

3377

4503

5629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

878

1756

2634

3512

4390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.817

Hom.:

14801

Bravo

AF:

0.812

Asia WGS

AF:

0.786

AC:

2734

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.76

(source)

DANN

Benign

0.56

PhyloP100

-0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over