rs147182852

Variant names:

• chr8-1770604-C-G
• rs147182852
• NM_018941.4:c.-123-328C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-1770604-C-G
• chr8-1770604-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018941.4(CLN8):​c.-123-328C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 152,176 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.013 (17 hom., cov: 32)
• Consequence: CLN8 NM_018941.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04
• Publications: 0 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: Genomics England PanelApp, Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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=-0.93).
• BP6: Variant 8-1770604-C-G is Benign according to our data. Variant chr8-1770604-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 669706.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.013 (1972/152176) while in subpopulation NFE AF = 0.0177 (1202/67992). AF 95% confidence interval is 0.0168. There are 17 homozygotes in GnomAd4. There are 984 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018941.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN8	NM_018941.4	MANE Select	c.-123-328C>G		intron	N/A	NP_061764.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN8	ENST00000331222.6	TSL:1 MANE Select	c.-123-328C>G		intron	N/A	ENSP00000328182.4	Q9UBY8
	KBTBD11-OT1	ENST00000635855.1	TSL:5	n.-123-328C>G		intron	N/A	ENSP00000489726.1	A0A1B0GTJ5
	CLN8	ENST00000519254.2	TSL:5	c.-123-328C>G		intron	N/A	ENSP00000490016.1	Q9UBY8

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1972 AN: 152058 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0397

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0201

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

GnomAD4 genome AF: 0.0130 AC: 1972 AN: 152176 Hom.: 17 Cov.: 32 AF XY: 0.0132 AC XY: 984 AN XY: 74400

African (AFR) AF: 0.00275 AC: 114 AN: 41516

American (AMR) AF: 0.0109 AC: 167 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.0397 AC: 421 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0177 AC: 1202 AN: 67992

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.00460 Hom.: 0

Bravo AF: 0.0107

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.094
DANN	Benign	0.44
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs147182852; hg19: chr8-1718770;