8-1770805-C-T

Position:

• chr8-1770805-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018941.4(CLN8):​c.-123-127C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.802 in 586,928 control chromosomes in the GnomAD database, including 189,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49809 hom., cov: 32)
  • Exomes 𝑓: 0.80 (140033 hom.)
• Consequence: CLN8 NM_018941.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0460

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 8-1770805-C-T is Benign according to our data. Variant chr8-1770805-C-T is described in ClinVar as [Benign]. Clinvar id is 1181243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLN8	NM_018941.4	c.-123-127C>T		intron_variant		ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.-123-127C>T		intron_variant		1	NM_018941.4	ENSP00000328182	P1

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122690 AN: 152030 Hom.: 49760 Cov.: 32

Gnomad AFR AF: 0.848

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.753

Gnomad SAS AF: 0.780

Gnomad FIN AF: 0.824

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.802

GnomAD4 exome AF: 0.801 AC: 348112 AN: 434780 Hom.: 140033 AF XY: 0.801 AC XY: 182722 AN XY: 228108

Gnomad4 AFR exome AF: 0.848

Gnomad4 AMR exome AF: 0.599

Gnomad4 ASJ exome AF: 0.768

Gnomad4 EAS exome AF: 0.744

Gnomad4 SAS exome AF: 0.789

Gnomad4 FIN exome AF: 0.829

Gnomad4 NFE exome AF: 0.820

Gnomad4 OTH exome AF: 0.800

GnomAD4 genome AF: 0.807 AC: 122791 AN: 152148 Hom.: 49809 Cov.: 32 AF XY: 0.803 AC XY: 59737 AN XY: 74382

Gnomad4 AFR AF: 0.848

Gnomad4 AMR AF: 0.663

Gnomad4 ASJ AF: 0.766

Gnomad4 EAS AF: 0.754

Gnomad4 SAS AF: 0.780

Gnomad4 FIN AF: 0.824

Gnomad4 NFE AF: 0.818

Gnomad4 OTH AF: 0.802

Alfa AF: 0.801 Hom.: 5009

Bravo AF: 0.793

Asia WGS AF: 0.781 AC: 2717 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.6
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4875957; hg19: chr8-1718971;