rs368365607

Variant names:

• chr8-1771261-G-A
• rs368365607
• NM_018941.4:c.207G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_018941.4(CLN8):​c.207G>A​(p.Thr69Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CLN8 NM_018941.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.53
• 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 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 8-1771261-G-A is Benign according to our data. Variant chr8-1771261-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261062.
• BP7: Synonymous conserved (PhyloP=-1.53 with no splicing effect.

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.207G>A	p.Thr69Thr	synonymous	Exon 2 of 3	NP_061764.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLN8	ENST00000331222.6	TSL:1 MANE Select	c.207G>A	p.Thr69Thr	synonymous	Exon 2 of 3	ENSP00000328182.4	Q9UBY8
	KBTBD11-OT1	ENST00000635855.1	TSL:5	n.207G>A		non_coding_transcript_exon	Exon 2 of 30	ENSP00000489726.1	A0A1B0GTJ5
	CLN8	ENST00000519254.2	TSL:5	c.207G>A	p.Thr69Thr	synonymous	Exon 2 of 3	ENSP00000490016.1	Q9UBY8

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251394 AF XY: 0.000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000204 AC: 298 AN: 1461548 Hom.: 0 Cov.: 32 AF XY: 0.000213 AC XY: 155 AN XY: 727020

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39688

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000880 AC: 47 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000203 AC: 226 AN: 1111708

Other (OTH) AF: 0.000116 AC: 7 AN: 60386

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74436

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Neuronal ceroid lipofuscinosis (1)
-	-	1	Neuronal ceroid lipofuscinosis 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.68
PhyloP100		-1.5
Mutation Taster		=98/2	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: rs368365607; hg19: chr8-1719427; COSMIC: COSV58669784; COSMIC: COSV58669784;