rs4875960

Positions:

• chr8-1800000-A-G
• chr8-1800000-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000635855.1(KBTBD11-OT1):​n.543+28403A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.843 in 151,990 control chromosomes in the GnomAD database, including 54,675 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 0.84 (54674 hom., cov: 31)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: KBTBD11-OT1 ENST00000635855.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.06

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.1800000A>G		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KBTBD11-OT1	ENST00000635855.1	n.543+28403A>G		intron_variant		5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128041 AN: 151870 Hom.: 54618 Cov.: 31

Gnomad AFR AF: 0.954

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.791

Gnomad EAS AF: 0.756

Gnomad SAS AF: 0.797

Gnomad FIN AF: 0.837

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.824

Gnomad OTH AF: 0.830

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.843 AC: 128151 AN: 151988 Hom.: 54674 Cov.: 31 AF XY: 0.840 AC XY: 62390 AN XY: 74280

Gnomad4 AFR AF: 0.954

Gnomad4 AMR AF: 0.683

Gnomad4 ASJ AF: 0.791

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.796

Gnomad4 FIN AF: 0.837

Gnomad4 NFE AF: 0.824

Gnomad4 OTH AF: 0.831

Alfa AF: 0.835 Hom.: 4953

Bravo AF: 0.834

Asia WGS AF: 0.803 AC: 2791 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.21
DANN	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4875960; hg19: chr8-1748166;