rs6558541

Positions:

• chr8-1800775-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
		n.1800775A>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD11-OT1	ENST00000635855.1	n.543+29178A>G		intron_variant		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

Gnomad4 AFR exome AF: 0.800

Gnomad4 AMR exome AF: 0.590

Gnomad4 ASJ exome AF: 0.753

Gnomad4 EAS exome AF: 0.630

Gnomad4 SAS exome AF: 0.594

Gnomad4 FIN exome AF: 0.710

Gnomad4 NFE exome AF: 0.748

Gnomad4 OTH exome AF: 0.736

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

Gnomad4 AFR AF: 0.789

Gnomad4 AMR AF: 0.631

Gnomad4 ASJ AF: 0.747

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.689

Gnomad4 NFE AF: 0.744

Gnomad4 OTH AF: 0.756

Alfa AF: 0.739 Hom.: 3875

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

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 15, 2024

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs6558541; hg19: chr8-1748941;