rs6558541

Variant names:

• chr8-1800775-A-G
• rs6558541
• ENST00000635855.1:n.543+29178A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000635855.1(KBTBD11-OT1):​n.543+29178A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 398,308 control chromosomes in the GnomAD database, including 107,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.74 (41419 hom., cov: 31)
  • Exomes 𝑓: 0.73 (65704 hom.)
• Consequence: KBTBD11-OT1 ENST00000635855.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.161
• Publications: 2 publications found

Genes affected

KBTBD11-OT1 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-1800775-A-G is Benign according to our data. Variant chr8-1800775-A-G is described in ClinVar as Benign. ClinVar VariationId is 3255238.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KBTBD11-OT1	ENST00000635855.1	n.543+29178A>G		intron_variant	Intron 2 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111718 AN: 151870 Hom.: 41398 Cov.: 31

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.632

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.601

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.742

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.755

GnomAD4 exome AF: 0.728 AC: 179300 AN: 246320 Hom.: 65704 Cov.: 0 AF XY: 0.729 AC XY: 91033 AN XY: 124812

African (AFR) AF: 0.800 AC: 5742 AN: 7178

American (AMR) AF: 0.590 AC: 4389 AN: 7434

Ashkenazi Jewish (ASJ) AF: 0.753 AC: 6954 AN: 9238

East Asian (EAS) AF: 0.630 AC: 14414 AN: 22892

South Asian (SAS) AF: 0.594 AC: 1801 AN: 3032

European-Finnish (FIN) AF: 0.710 AC: 14777 AN: 20816

Middle Eastern (MID) AF: 0.739 AC: 956 AN: 1294

European-Non Finnish (NFE) AF: 0.748 AC: 118223 AN: 158066

Other (OTH) AF: 0.736 AC: 12044 AN: 16370

GnomAD4 genome AF: 0.735 AC: 111781 AN: 151988 Hom.: 41419 Cov.: 31 AF XY: 0.728 AC XY: 54076 AN XY: 74294

African (AFR) AF: 0.789 AC: 32704 AN: 41424

American (AMR) AF: 0.631 AC: 9640 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2592 AN: 3470

East Asian (EAS) AF: 0.698 AC: 3607 AN: 5164

South Asian (SAS) AF: 0.601 AC: 2895 AN: 4816

European-Finnish (FIN) AF: 0.689 AC: 7272 AN: 10548

Middle Eastern (MID) AF: 0.736 AC: 215 AN: 292

European-Non Finnish (NFE) AF: 0.744 AC: 50569 AN: 67974

Other (OTH) AF: 0.756 AC: 1595 AN: 2110

Alfa AF: 0.739 Hom.: 161296

Bravo AF: 0.734

Asia WGS AF: 0.644 AC: 2238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 80% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 74. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.50
PhyloP100		-0.16

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs6558541; hg19: chr8-1748941;