8-1763883-C-T

Variant names:

• chr8-1763883-C-T
• rs113428006
• NM_018941.4:c.-126C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018941.4(CLN8):​c.-126C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 152,076 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (440 hom., cov: 28)
  • Exomes 𝑓: 0.068 (1 hom.)
• Consequence: CLN8 NM_018941.4 splice_region
• Scores: Splicing: ADA: 0.001860
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.120
• Publications: 1 publications found

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-AS1 (HGNC:55523): (CLN8 antisense RNA 1)

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 8-1763883-C-T is Benign according to our data. Variant chr8-1763883-C-T is described in ClinVar as [Benign]. Clinvar id is 136808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN8	NM_018941.4	c.-126C>T		splice_region_variant	Exon 1 of 3	ENST00000331222.6	NP_061764.2
CLN8	NM_018941.4	c.-126C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.-126C>T		splice_region_variant	Exon 1 of 3	1	NM_018941.4	ENSP00000328182.4
CLN8	ENST00000331222.6	c.-126C>T		5_prime_UTR_variant	Exon 1 of 3	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.-182C>T		upstream_gene_variant		5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9800 AN: 150900 Hom.: 441 Cov.: 28

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0457

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0425

Gnomad NFE AF: 0.0776

Gnomad OTH AF: 0.0551

GnomAD4 exome AF: 0.0675 AC: 72 AN: 1066 Hom.: 1 Cov.: 0 AF XY: 0.0625 AC XY: 50 AN XY: 800

African (AFR) AF: 0.00 AC: 0 AN: 14

American (AMR) AF: 0.00 AC: 0 AN: 10

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.214 AC: 6 AN: 28

South Asian (SAS) AF: 0.0854 AC: 7 AN: 82

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.0645 AC: 56 AN: 868

Other (OTH) AF: 0.0652 AC: 3 AN: 46

GnomAD4 genome AF: 0.0649 AC: 9796 AN: 151010 Hom.: 440 Cov.: 28 AF XY: 0.0700 AC XY: 5167 AN XY: 73792

African (AFR) AF: 0.0144 AC: 595 AN: 41218

American (AMR) AF: 0.0330 AC: 502 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.0457 AC: 158 AN: 3458

East Asian (EAS) AF: 0.154 AC: 763 AN: 4964

South Asian (SAS) AF: 0.191 AC: 915 AN: 4792

European-Finnish (FIN) AF: 0.128 AC: 1347 AN: 10492

Middle Eastern (MID) AF: 0.0493 AC: 14 AN: 284

European-Non Finnish (NFE) AF: 0.0776 AC: 5246 AN: 67598

Other (OTH) AF: 0.0564 AC: 118 AN: 2094

Alfa AF: 0.0642 Hom.: 50

Bravo AF: 0.0536

Asia WGS AF: 0.160 AC: 552 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 01, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.3
DANN	Benign	0.79
PhyloP100		0.12
PromoterAI		0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs113428006; hg19: chr8-1712049;