8-1798784-A-G

Variant names:

• chr8-1798784-A-G
• rs11986414
• ENST00000635855.1:n.543+27187A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000635855.1(KBTBD11-OT1):​n.543+27187A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.26 (525 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: KBTBD11-OT1 ENST00000635855.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.70
• Publications: 16 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.05).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000635855.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KBTBD11-OT1	ENST00000635855.1	TSL:5	n.543+27187A>G		intron	N/A	ENSP00000489726.1
	CLN8	ENST00000636934.1	TSL:5	c.544-1890A>G		intron	N/A	ENSP00000490218.1
	KBTBD11-OT1	ENST00000635773.1	TSL:5	n.495+27187A>G		intron	N/A	ENSP00000490620.1

Frequencies

GnomAD3 genomes AF: 0.260 AC: 2441 AN: 9390 Hom.: 518 Cov.: 0

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.282

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

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.261 AC: 2455 AN: 9404 Hom.: 525 Cov.: 0 AF XY: 0.270 AC XY: 1317 AN XY: 4878

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.374 AC: 722 AN: 1930

American (AMR) AF: 0.125 AC: 244 AN: 1954

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 55 AN: 232

East Asian (EAS) AF: 0.200 AC: 109 AN: 546

South Asian (SAS) AF: 0.307 AC: 116 AN: 378

European-Finnish (FIN) AF: 0.263 AC: 139 AN: 528

Middle Eastern (MID) AF: 0.563 AC: 9 AN: 16

European-Non Finnish (NFE) AF: 0.276 AC: 1019 AN: 3688

Other (OTH) AF: 0.310 AC: 39 AN: 126

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.814 Hom.: 60186

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.27
DANN	Benign	0.085
PhyloP100		-1.7

Splicing

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

Other links and lift over

dbSNP: rs11986414; hg19: chr8-1746950; COSMIC: COSV53502251; COSMIC: COSV53502251;