NM_018941.4:c.-123-127C>T

Variant names:

• chr8-1770805-C-T
• rs4875957
• NM_018941.4:c.-123-127C>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.-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
• 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 -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 rank	MANE	Protein	UniProt
CLN8	NM_018941.4	c.-123-127C>T		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.-123-127C>T		intron_variant	Intron 1 of 2	1	NM_018941.4	ENSP00000328182.4
KBTBD11-OT1	ENST00000635855.1	n.-123-127C>T		intron_variant	Intron 1 of 29	5		ENSP00000489726.1

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

African (AFR) AF: 0.848 AC: 10352 AN: 12206

American (AMR) AF: 0.599 AC: 11082 AN: 18514

Ashkenazi Jewish (ASJ) AF: 0.768 AC: 10400 AN: 13550

East Asian (EAS) AF: 0.744 AC: 22509 AN: 30260

South Asian (SAS) AF: 0.789 AC: 34288 AN: 43432

European-Finnish (FIN) AF: 0.829 AC: 23491 AN: 28322

Middle Eastern (MID) AF: 0.794 AC: 1519 AN: 1914

European-Non Finnish (NFE) AF: 0.820 AC: 214227 AN: 261268

Other (OTH) AF: 0.800 AC: 20244 AN: 25314

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

African (AFR) AF: 0.848 AC: 35188 AN: 41500

American (AMR) AF: 0.663 AC: 10120 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.766 AC: 2660 AN: 3472

East Asian (EAS) AF: 0.754 AC: 3902 AN: 5172

South Asian (SAS) AF: 0.780 AC: 3759 AN: 4820

European-Finnish (FIN) AF: 0.824 AC: 8727 AN: 10590

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55653 AN: 68008

Other (OTH) AF: 0.802 AC: 1695 AN: 2114

Alfa AF: 0.802 Hom.: 13383

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.6
DANN	Benign	0.30
PhyloP100		0.046
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4875957; hg19: chr8-1718971;