8-1770707-G-C

Variant names:

• chr8-1770707-G-C
• rs4875806
• NM_018941.4:c.-123-225G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_018941.4(CLN8):​c.-123-225G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 152,124 control chromosomes in the GnomAD database, including 49,566 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.81 (49566 hom., cov: 32)
• Consequence: CLN8 NM_018941.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.36
• Publications: 4 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 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

KBTBD11-OT1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 8-1770707-G-C is Benign according to our data. Variant chr8-1770707-G-C is described in ClinVar as [Benign]. Clinvar id is 1279902.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLN8	NM_018941.4	c.-123-225G>C		intron_variant	Intron 1 of 2	ENST00000331222.6	NP_061764.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLN8	ENST00000331222.6	c.-123-225G>C		intron_variant	Intron 1 of 2	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.-123-225G>C		intron_variant	Intron 1 of 29	5		ENSP00000489726.1

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122385 AN: 152008 Hom.: 49518 Cov.: 32

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.940

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.766

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.779

Gnomad FIN AF: 0.825

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.800

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

GnomAD4 genome AF: 0.805 AC: 122484 AN: 152124 Hom.: 49566 Cov.: 32 AF XY: 0.801 AC XY: 59583 AN XY: 74366

African (AFR) AF: 0.843 AC: 34977 AN: 41496

American (AMR) AF: 0.662 AC: 10099 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2658 AN: 3470

East Asian (EAS) AF: 0.753 AC: 3893 AN: 5168

South Asian (SAS) AF: 0.779 AC: 3757 AN: 4824

European-Finnish (FIN) AF: 0.825 AC: 8729 AN: 10586

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55594 AN: 67996

Other (OTH) AF: 0.801 AC: 1692 AN: 2112

Alfa AF: 0.781 Hom.: 2469

Bravo AF: 0.791

Asia WGS AF: 0.781 AC: 2716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.063
DANN	Benign	0.49
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4875806; hg19: chr8-1718873;